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Cold Spring Harbor Perspectives in Biology
Journal Prestige (SJR): 7.471  Citation Impact (citeScore): 10 Number of Followers: 3  Subscription journalISSN (Online) 1943-0264 Published by Cold Spring Harbor Lab Press  [8 journals]
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- [Early Release Articles] Beyond the Code: Noncoding RNAs in Skin Wound
Healing-
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Authors: Li, D; Niu, G, Landen, N. X.
Abstract: An increasing number of noncoding RNAs (ncRNAs) have been found to regulate gene expression and protein functions, playing important roles in diverse biological processes and diseases. Their crucial functions have been reported in almost every cell type and all stages of skin wound healing. Evidence of their pathogenetic roles in common wound complications, such as chronic nonhealing wounds and excessive scarring, is also accumulating. Given their unique expression and functional properties, ncRNAs are promising therapeutic and diagnostic entities. In this review, we discuss current knowledge about the functional roles of noncoding elements, such as microRNAs, long ncRNAs, and circular RNAs, in skin wound healing, focusing on in vivo evidence from studies of human wound samples and animal wound models. Finally, we provide a perspective on the outlook of ncRNA-based therapeutics in wound care.
Keywords: Wound Healing: From Bench to Bedside
PubDate: 2022-02-23T07:49:09-08:00
DOI: 10.1101/cshperspect.a041230
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- [Early Release Articles] Sex Differences in Circadian Rhythms
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Authors: Walton, J. C; Bumgarner, J. R, Nelson, R. J.
Abstract: Sex as a biological variable is the focus of much literature and has been emphasized by the National Institutes of Health, in part, to remedy a long history of male-dominated studies in preclinical and clinical research. We propose that time-of-day is also a crucial biological variable in biomedical research. In common with sex differences, time-of-day should be considered in analyses and reported to improve reproducibility of studies and to provide the appropriate context to the conclusions. Endogenous circadian rhythms are present in virtually all living organisms, including bacteria, plants, invertebrates, and vertebrates. Virtually all physiological and behavioral processes display daily fluctuations in optimal performance that are driven by these endogenous circadian clocks; importantly, many of those circadian rhythms also show sex differences. In this review, we describe some of the documented sex differences in circadian rhythms.
Keywords: Sex Differences in Brain and Behavior
PubDate: 2022-01-31T12:15:47-08:00
DOI: 10.1101/cshperspect.a039107
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- [Early Release Articles] Wound Healing from an Actin Cytoskeletal
Perspective-
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Authors: Ahangar, P; Strudwick, X. L, Cowin, A. J.
Abstract: Wound healing requires a complex cascade of highly controlled and conserved cellular and molecular processes. These involve numerous cell types and extracellular matrix molecules regulated by the actin cytoskeleton. This microscopic network of filaments is present within the cytoplasm of all cells and provides the shape and mechanical support required for cell movement and proliferation. Here, an overview of the processes of wound healing are described from the perspective of the cell in relation to the actin cytoskeleton. Key points of discussion include the role of actin, its binding proteins, signaling pathways, and events that play significant roles in the phases of wound healing. The identification of cytoskeletal targets that can be used to manipulate and improve wound healing is included as an emerging area of focus that may inform future therapeutic approaches to improve healing of complex wounds.
PubDate: 2022-01-24T06:20:20-08:00
DOI: 10.1101/cshperspect.a041235
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- [Early Release Articles] Somatic Lineage Reprogramming
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Authors: Shelby, H; Shelby, T, Wernig, M.
Abstract: Embryonic development and cell specification have been viewed as an epigenetically rigid process. Through accumulation of irreversible epigenetic marks, the differentiation process has been considered unidirectional, and once completed cell specification would be permanent and stable. However, somatic cell nuclear transfer that involved the implantation of a somatic nucleus into a previously enucleated oocyte accomplished in amphibians in the 1950s and in mammals in the late 1990s—resulting in the birth of "Dolly the sheep"—clearly showed that "terminal" differentiation is reversible. In parallel, work on lineage-determining factors like MyoD revealed surprising potential to modulate lineage identity in somatic cells. This work culminated in the discovery that a set of four defined factors can reprogram fibroblasts into induced pluripotent stem (iPS) cells, which were shown to be molecularly and functionally equivalent to blastocyst-derived embryonic stem (ES) cells, thus essentially showing that defined factors can induce authentic reprogramming without the need of oocytes. This concept was further extended when it was shown that fibroblasts can be directly converted into neurons, showing induced lineage conversion is possible even between cells representing two different germ layers. These findings suggest that "everything is possible" (i.e., once key lineage reprogramming factors are identified, cells should be able to convert into any desired lineage).
Keywords: Regeneration
PubDate: 2021-12-06T12:50:23-08:00
DOI: 10.1101/cshperspect.a040808
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- [Early Release Articles] Imaginal Disc Regeneration: Something Old,
Something New-
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Authors: Worley, M. I; Hariharan, I. K.
Abstract: Imaginal discs are simple epithelial sacs found in Drosophila larvae, which generate adult structures including wings and legs. The first studies of imaginal disc regeneration involved technically challenging transplantation experiments. Yet despite the difficulty, many aspects of regeneration including wound healing, blastema formation, and the repatterning of regenerated tissue were characterized. An important discovery was the phenomenon of transdetermination, where a small group of cells in regenerating tissue collectively switch fate ("collective cell reprogramming"). The development of genetic tissue-ablation systems over the last 12 years has energized this field, by making experiments less technically challenging, more reproducible, and by incorporating additional genetic analysis. Recent progress includes defining mechanistic links between early responses to wounding and the signaling pathways that drive proliferation, uncovering a role for localized silencing of damage-responsive enhancers to limit regenerative capacity as tissues mature, and identifying genes that maintain cellular plasticity within acceptable limits during regeneration.
Keywords: Regeneration
PubDate: 2021-12-06T12:50:23-08:00
DOI: 10.1101/cshperspect.a040733
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- [Early Release Articles] Evidence for Perinatal Steroid Influence on Human
Sexual Orientation and Gendered Behavior-
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Authors: Swift-Gallant, A; Shirazi, T, Puts, D. A, Breedlove, S. M.
Abstract: In laboratory animals, exposure to gonadal steroid hormones before and immediately after birth can exert permanent effects on many behaviors, particularly reproductive behaviors. The extent to which such effects occur in humans remains an open question, but several lines of evidence indicate that perinatal levels of both androgens and estrogens may affect adult human psychology and behavior, including sexual orientation and gender nonconformity. Some putative indicators of prenatal androgen exposure, including the ratio of the length of the index finger to that of the ring finger (2D:4D), have repeatedly indicated that lesbians, on average, were exposed to more prenatal androgens than straight women, suggesting that sufficient fetal androgen exposure predisposes a fetus to gynephilia (attraction to women) at maturity. The digit ratios of gay men do not differ from those of straight men, suggesting that prenatal androgen levels are not responsible for their androphilia (attraction to men). However, evidence that gay men who prefer an insertive anal sex role (ASR) have more masculine digit ratios than those preferring a receptive ASR suggests that early androgens influence some sexual preferences in men. Furthermore, digit ratios among gay men have been found to correlate with recalled childhood gender nonconformity (CGN). People with isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) offer further insight into the effects of perinatal gonadal steroid exposure. In people with IGD, gonadal hormone production is low or absent after the first trimester of gestation. However, because placental gonadotropins drive gonadal hormone secretion during the first trimester when genitalia sexually differentiate, individuals with IGD are unambiguously male or female at birth, consistent with their chromosomal and gonadal sex. Men with IGD report greater CGN, again suggesting that perinatal androgen exposure contributes to male-typical behavioral patterns in humans. Interestingly, women with IGD report less androphilia and more bisexuality than control women, suggesting that perinatal ovarian steroids in females typically augment androphilia in adulthood. Taken together, these findings indicate that the perinatal hormonal milieu influences human sexual orientation and gender conformity.
Keywords: Sex Differences in Brain and Behavior
PubDate: 2021-12-06T12:50:23-08:00
DOI: 10.1101/cshperspect.a039123
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- [Early Release Articles] Fairly Criticized, or Politicized' Conflicts
in the Neuroscience of Sex Differences in the Human Brain-
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Authors: Fine; C.
Abstract: Investigations of sex differences in the human brain take place on politically sensitive terrain. While some scholars express concern that gendered biases and stereotypes remain embedded in scientific research, others are alarmed about the politicization of science. To help better understand these debates, this review sets out three kinds of conflicts that can arise in the neuroscience of sex differences: academic freedom versus gender equality; frameworks, background assumptions, and dominant methodologies; and inductive risk and social values. The boundaries between fair criticism and politicization are explored for each kind of conflict, pointing to ways in which the academic community can facilitate fair criticism while protecting against politicization.
Keywords: Sex Differences in Brain and Behavior
PubDate: 2021-12-06T12:50:23-08:00
DOI: 10.1101/cshperspect.a039115
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- [Early Release Articles] The Diverse Manifestations of Regeneration and
Why We Need to Study Them-
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Authors: Sasidharan, V; Sanchez Alvarado, A.
Abstract: For hundreds of years, the question of why some organisms can regenerate missing body parts while others cannot has remained poorly understood. This has been due in great part to the inability to genetically, molecularly, and cellularly dissect this problem for most of the history of the field. It has only been in the past 20–30 years that important mechanistic advances have been made in methodologies that introduce loss and gain of gene function in animals that can regenerate. However, we still have a very incomplete understanding of how broadly regenerative abilities may be dispersed across species and whether or not such properties share a common evolutionary origin, which may have emerged independently or both. Understanding regeneration, therefore, will require rigorously practiced fundamental, curiosity-driven, discovery research. Expanding the number of research organisms used to study regeneration allows us to uncover aspects of this problem we may not yet know exist and simultaneously increases our chances of solving this long-standing problem of biology.
Keywords: Regeneration
PubDate: 2021-11-08T08:49:03-08:00
DOI: 10.1101/cshperspect.a040931
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- [Early Release Articles] Lung Regeneration: Cells, Models, and Mechanisms
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Authors: Konkimalla, A; Tata, A, Tata, P. R.
Abstract: Lung epithelium, the lining that covers the inner surface of the respiratory tract, is directly exposed to the environment and thus susceptible to airborne toxins, irritants, and pathogen-induced damages. In adult mammalian lungs, epithelial cells are generally quiescent but can respond rapidly to repair of damaged tissues. Evidence from experimental injury models in rodents and human clinical samples has led to the identification of these regenerative cells, as well as pathological metaplastic states specifically associated with different forms of damages. Here, we provide a compendium of cells and cell states that exist during homeostasis in normal lungs and the lineage relationships between them. Additionally, we discuss various experimental injury models currently being used to probe the cellular sources—both resident and recruited—that contribute to repair, regeneration, and remodeling following acute and chronic injuries. Finally, we discuss certain maladaptive regeneration-associated cell states and their role in disease pathogenesis.
Keywords: Regeneration
PubDate: 2021-11-08T08:49:03-08:00
DOI: 10.1101/cshperspect.a040873
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- [Early Release Articles] Genetic and Cellular Contributions to Liver
Regeneration-
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Authors: Liang, R; Lin, Y.-H, Zhu, H.
Abstract: The regenerative capabilities of the liver represent a paradigm for understanding tissue repair in solid organs. Regeneration after partial hepatectomy in rodent models is well understood, while regeneration in the context of clinically relevant chronic injuries is less studied. Given the growing incidence of fatty liver disease, cirrhosis, and liver cancer, interest in liver regeneration is increasing. Here, we will review the principles, genetics, and cell biology underlying liver regeneration, as well as new approaches being used to study heterogeneity in liver tissue maintenance and repair.
Keywords: Regeneration
PubDate: 2021-11-08T08:49:03-08:00
DOI: 10.1101/cshperspect.a040832
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- [Early Release Articles] All for One and One for All: Regenerating
Skeletal Muscle-
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Authors: Hindi, S. M; Millay, D. P.
Abstract: Despite the evolutionary loss of tissue regenerative potential, robust skeletal muscle repair processes are largely retained even in higher vertebrates. In mammals, the skeletal muscle regeneration program is driven by resident stem cells termed satellite cells, guided by the coordinated activity of multiple intrinsic and extrinsic factors and other cell types. A thorough understanding of muscle repair mechanisms is crucial not only for combating skeletal myopathies, but for its prospective aid in devising therapeutic strategies to endow regenerative potential on otherwise regeneration-deficient organs. In this review, we discuss skeletal muscle regeneration from an evolutionary perspective, summarize the current knowledge of cellular and molecular mechanisms, and highlight novel paradigms of muscle repair revealed by explorations of the recent decade.
Keywords: Regeneration
PubDate: 2021-11-08T08:49:03-08:00
DOI: 10.1101/cshperspect.a040824
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- [Early Release Articles] Hematopoietic Stem Cells and Regeneration
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Authors: Biermann, M; Reya, T.
Abstract: Hematopoietic stem cell (HSC) regeneration is the remarkable process by which extremely rare, normally inactive cells of the bone marrow can replace an entire organ if called to do so by injury or harnessed by transplantation. HSC research is arguably the first quantitative single-cell science and the foundation of adult stem cell biology. Bone marrow transplant is the oldest and most refined technique of regenerative medicine. Here we review the intertwined history of the discovery of HSCs and bone marrow transplant, the molecular and cellular mechanisms of HSC self-renewal, and the use of HSCs and their derivatives for cell therapy.
Keywords: Regeneration
PubDate: 2021-11-08T08:49:03-08:00
DOI: 10.1101/cshperspect.a040774
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- [Early Release Articles] Sex Differences in Spotted Hyenas
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Authors: McCormick, S. K; Holekamp, K. E, Smale, L, Weldele, M. L, Glickman, S. E, Place, N. J.
Abstract: The apparent virilization of the female spotted hyena raises questions about sex differences in behavior and morphology. We review these sex differences to find a mosaic of dimorphic traits, some of which conform to mammalian norms. These include space-use, dispersal behavior, sexual behavior, and parental behavior. By contrast, sex differences are reversed from mammalian norms in the hyena's aggressive behavior, social dominance, and territory defense. Androgen exposure early in development appears to enhance aggressiveness in female hyenas. Weapons, hunting behavior, and neonatal body mass do not differ between males and females, but females are slightly larger than males as adults. Sex differences in the hyena's nervous system are relatively subtle. Overall, it appears that the "masculinized" behavioral traits in female spotted hyenas are those, such as aggression, that are essential to ensuring consistent access to food; food critically limits female reproductive success in this species because female spotted hyenas have the highest energetic investment per litter of any mammalian carnivore. Evidently, natural selection has acted to modify traits related to food access, but has left intact those traits that are unrelated to acquiring food, such that they conform to patterns of sexual dimorphism in other mammals.
Keywords: Sex Differences in Brain and Behavior
PubDate: 2021-11-02T07:45:16-07:00
DOI: 10.1101/cshperspect.a039180
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- [Early Release Articles] Zebrafish Fin: Complex Molecular Interactions and
Cellular Mechanisms Guiding Regeneration-
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Authors: Sehring, I; Weidinger, G.
Abstract: The zebrafish caudal fin has become a popular model to study cellular and molecular mechanisms of regeneration due to its high regenerative capacity, accessibility for experimental manipulations, and relatively simple anatomy. The formation of a regenerative epidermis and blastema are crucial initial events and tightly regulated. Both the regenerative epidermis and the blastema are highly organized structures containing distinct domains, and several signaling pathways regulate the formation and interaction of these domains. Bone is the major tissue regenerated from the progenitor cells of the blastema. Several cellular mechanisms can provide source cells for blastemal (pre-)osteoblasts, including dedifferentiation of differentiated osteoblasts and de novo formation from other cell types, providing intriguing examples of cellular plasticity. In recent years, omics analyses and single-cell approaches have elucidated genetic and epigenetic regulation, increasing our knowledge of the surprisingly complex coordination of various mechanisms to achieve successful restoration of a seemingly simple structure.
Keywords: Regeneration
PubDate: 2021-10-14T08:56:03-07:00
DOI: 10.1101/cshperspect.a040758
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- [Early Release Articles] Pervasive Neglect of Sex Differences in
Biomedical Research-
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Authors: Zucker, I; Prendergast, B. J, Beery, A. K.
Abstract: Females have long been underrepresented in preclinical research and clinical drug trials. Directives by the U.S. National Institutes of Health have increased female participation in research protocols, although analysis of outcomes by sex remains infrequent. The long-held view that traits of female rats and mice are more variable than those of males is discredited, supporting equal representation of both sexes in most studies. Drug pharmacokinetic analysis reveals that, among subjects administered a standard drug dose, women are exposed to higher blood drug concentrations and longer drug elimination times. This contributes to increased adverse drug reactions in women and suggests that women are routinely overmedicated and should be administered lower drug doses than men. The past decade has seen progress in female inclusion, but key subsequent steps such as sex-based analysis and sex-specific drug dosing remain to be implemented.
Keywords: Sex Differences in Brain and Behavior
PubDate: 2021-10-14T08:56:03-07:00
DOI: 10.1101/cshperspect.a039156
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- [Early Release Articles] Positional Memory in Vertebrate Regeneration: A
Century's Insights from the Salamander Limb-
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Authors: Otsuki, L; Tanaka, E. M.
Abstract: Salamanders, such as axolotls and newts, can regenerate complex tissues including entire limbs. But what mechanisms ensure that an amputated limb regenerates a limb, and not a tail or unpatterned tissue' An important concept in regeneration is positional memory—the notion that adult cells "remember" spatial identities assigned to them during embryogenesis (e.g., "head" or "hand") and use this information to restore the correct body parts after injury. Although positional memory is well documented at a phenomenological level, the underlying cellular and molecular bases are just beginning to be decoded. Herein, we review how major principles in positional memory were established in the salamander limb model, enabling the discovery of positional memory-encoding molecules, and advancing insights into their pattern-forming logic during regeneration. We explore findings in other amphibians, fish, reptiles, and mammals and speculate on conserved aspects of positional memory. We consider the possibility that manipulating positional memory in human cells could represent one route toward improved tissue repair or engineering of patterned tissues for therapeutic purposes.
Keywords: Regeneration
PubDate: 2021-10-04T08:39:49-07:00
DOI: 10.1101/cshperspect.a040899
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- [Early Release Articles] Building and Maintaining the Skin
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Authors: Hsu, Y.-C; Fuchs, E.
Abstract: The skin forms a crucial, dynamic barrier between an animal and the external world. In mammals, three stem cell populations possess robust regenerative potential to maintain and repair the body's protective surface: epidermal stem cells, which maintain the stratified epidermis; hair follicle stem cells, which power the cyclic growth of the hair follicle; and melanocyte stem cells, which regenerate pigment-producing melanocytes to color the skin and hair. These stem cells reside in complex microenvironments ("niches") comprising diverse cellular repertoires that enable stem cells to rejuvenate tissues during homeostasis and regenerate them upon injury. Beyond their niches, skin stem cells can also sense and respond to fluctuations in organismal health or changes outside the body. Here, we review these diverse cellular interactions and highlight how far-reaching signals can be transmitted at the local level to enable skin stem cells to tailor their actions to suit the particular occasion and optimize fitness.
Keywords: Regeneration
PubDate: 2021-10-04T08:39:49-07:00
DOI: 10.1101/cshperspect.a040840
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- [Early Release Articles] Quantifying Sex Differences in Behavior in the
Era of "Big" Data-
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Authors: Trainor, B. C; Falkner, A. L.
Abstract: Sex differences are commonly observed in behaviors that are closely linked to adaptive function, but sex differences can also be observed in behavioral "building blocks" such as locomotor activity and reward processing. Modern neuroscientific inquiry, in pursuit of generalizable principles of functioning across sexes, has often ignored these more subtle sex differences in behavioral building blocks that may result from differences in these behavioral building blocks. A frequent assumption is that there is a default (often male) way to perform a behavior. This approach misses fundamental drivers of individual variability within and between sexes. Incomplete behavioral descriptions of both sexes can lead to an overreliance on reduced "single-variable" readouts of complex behaviors, the design of which may be based on male-biased samples. Here, we advocate that the incorporation of new machine-learning tools for collecting and analyzing multimodal "big behavior" data allows for a more holistic and richer approach to the quantification of behavior in both sexes. These new tools make behavioral description more robust and replicable across laboratories and species, and may open up new lines of neuroscientific inquiry by facilitating the discovery of novel behavioral states. Having more accurate measures of behavioral diversity in males and females could serve as a hypothesis generator for where and when we should look in the brain for meaningful neural differences.
Keywords: Sex Differences in Brain and Behavior
PubDate: 2021-10-04T08:39:49-07:00
DOI: 10.1101/cshperspect.a039164
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- [Early Release Articles] Good Neighbors: The Niche that Fine Tunes
Mammalian Intestinal Regeneration-
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Authors: Palikuqi, B; Rispal, J, Klein, O.
Abstract: The intestinal epithelium undergoes continuous cellular turnover, making it an attractive model to study tissue renewal and regeneration. Intestinal stem cells (ISCs) can both self-renew and differentiate along all epithelial cell lineages. Decisions about which fate to pursue are controlled by a balance between high Wnt signaling at the crypt bottom, where Lgr5+ ISCs reside, and increasing bone morphogenetic protein (BMP) levels toward the villus, where differentiated cells are located. Under stress conditions, epithelial cells in the intestine are quite plastic, with dedifferentiation, the reversal of cell fate from a differentiated cell to a more stem-like cell, allowing for most mature epithelial cell types to acquire stem cell–like properties. The ISC niche, mainly made up of mesenchymal, immune, enteric neuronal, and endothelial cells, plays a central role in maintaining the physiological function of the intestine. Additionally, the immune system and the microbiome play an essential role in regulating intestinal renewal. The development of various mouse models, organoid co-cultures and single-cell technologies has led to advances in understanding signals emanating from the mesenchymal niche. Here, we review how intestinal regeneration is driven by stem cell self-renewal and differentiation, with an emphasis on the niche that fine tunes these processes in both homeostasis and injury conditions.
Keywords: Regeneration
PubDate: 2021-09-27T08:28:02-07:00
DOI: 10.1101/cshperspect.a040865
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- [Early Release Articles] Comparative Biology of Vertebrate Retinal
Regeneration: Restoration of Vision through Cellular Reprogramming-
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Authors: Todd, L; Reh, T. A.
Abstract: The regenerative capacity of the vertebrate retina varies substantially across species. Whereas fish and amphibians can regenerate functional retina, mammals do not. In this perspective piece, we outline the various strategies nonmammalian vertebrates use to achieve functional regeneration of vision. We review key differences underlying the regenerative potential across species including the cellular source of postnatal progenitors, the diversity of cell fates regenerated, and the level of functional vision that can be achieved. Finally, we provide an outlook on the field of engineering the mammalian retina to replace neurons lost to injury or disease.
Keywords: Regeneration
PubDate: 2021-09-27T08:28:02-07:00
DOI: 10.1101/cshperspect.a040816
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- [Early Release Articles] Pancreatic {beta}-Cell Development and
Regeneration-
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Authors: Kerper, N; Ashe, S, Hebrok, M.
Abstract: The pancreatic β-cells are essential for regulating glucose homeostasis through the coordinated release of the insulin hormone. Dysfunction of the highly specialized β-cells results in diabetes mellitus, a growing global health epidemic. In this review, we describe the development and function of β-cells the emerging concept of heterogeneity within insulin-producing cells, and the potential of other cell types to assume β-cell functionality via transdifferentiation. We also discuss emerging routes to design cells with minimal β-cell properties and human stem cell differentiation efforts that carry the promise to restore normoglycemia in patients suffering from diabetes.
Keywords: Regeneration
PubDate: 2021-09-27T08:28:02-07:00
DOI: 10.1101/cshperspect.a040741
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- [Early Release Articles] Axon Regeneration: A Subcellular Extension in
Multiple Dimensions-
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Authors: Winter, C. C; He, Z, Jacobi, A.
Abstract: Axons are a unique cellular structure that allows for the communication between neurons. Axon damage compromises neuronal communications and often leads to functional deficits. Thus, developing strategies that promote effective axon regeneration for functional restoration is highly desirable. One fruitful approach is to dissect the regenerative mechanisms used by some types of neurons in both mammalian and nonmammalian systems that exhibit spontaneous regenerative capacity. Additionally, numerous efforts have been devoted to deciphering the barriers that prevent successful axon regeneration in the most regeneration-refractory system—the adult mammalian central nervous system. As a result, several regeneration-promoting strategies have been developed, but significant limitations remain. This review is aimed to summarize historic progression and current understanding of this exciting yet incomplete endeavor.
Keywords: Regeneration
PubDate: 2021-09-13T12:31:23-07:00
DOI: 10.1101/cshperspect.a040923
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- [Early Release Articles] Positional Information and Stem Cells Combine to
Result in Planarian Regeneration-
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Authors: Reddien; P. W.
Abstract: The capacity for regeneration is broad in the animal kingdom. Planarians are flatworms that can regenerate any missing body part and their regenerative powers have combined with ease of experimentation to make them a classic regeneration model for more than a century. Pluripotent stem cells called neoblasts generate missing planarian tissues. Fate specification happens in the neoblasts, and this can occur in response to regeneration instructions in the form of positional information. Fate specification can lead to differentiating cells in single steps rather than requiring a long lineage hierarchy. Planarians display constitutive expression of positional information from muscle cells, which is required for patterned maintenance of tissues in tissue turnover. Amputation leads to the rapid resetting of positional information in a process triggered by wound signaling and the resetting of positional information is required for regeneration. These findings suggest a model for planarian regeneration in which adult positional information resets after injury to regulate stem cells to bring about the replacement of missing parts.
Keywords: Regeneration
PubDate: 2021-09-13T12:31:23-07:00
DOI: 10.1101/cshperspect.a040717
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- [Early Release Articles] Mechanisms of Chromosome Folding and Nuclear
Organization: Their Interplay and Open Questions-
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Authors: Mirny, L; Dekker, J.
Abstract: Microscopy and genomic approaches provide detailed descriptions of the three-dimensional folding of chromosomes and nuclear organization. The fundamental question is how activity of molecules at the nanometer scale can lead to complex and orchestrated spatial organization at the scale of chromosomes and the whole nucleus. At least three key mechanisms can bridge across scales: (1) tethering of specific loci to nuclear landmarks leads to massive reorganization of the nucleus; (2) spatial compartmentalization of chromatin, which is driven by molecular affinities, results in spatial isolation of active and inactive chromatin; and (3) loop extrusion activity of SMC (structural maintenance of chromosome) complexes can explain many features of interphase chromatin folding and underlies key phenomena during mitosis. Interestingly, many features of chromosome organization ultimately result from collective action and the interplay between these mechanisms, and are further modulated by transcription and topological constraints. Finally, we highlight some outstanding questions that are critical for our understanding of nuclear organization and function. We believe many of these questions can be answered in the coming years.
Keywords: The Nucleus
PubDate: 2021-09-13T12:31:23-07:00
DOI: 10.1101/cshperspect.a040147
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- [Early Release Articles] Sex Differences in Major Depressive Disorder
(MDD) and Preclinical Animal Models for the Study of Depression-
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Authors: Williams, E. S; Mazei-Robison, M, Robison, A. J.
Abstract: Depression and related mood disorders constitute an enormous burden on health, quality of life, and the global economy, and women have roughly twice the lifetime risk of men for experiencing depression. Here, we review sex differences in human brain physiology that may be connected to the increased susceptibility of women to major depressive disorder (MDD). Moreover, we summarize decades of preclinical research using animal models for the study of mood dysfunction that uncover some of the potential molecular, cellular, and circuit-level mechanisms that may underlie sex differences and disease etiology. We place particular emphasis on a series of recent studies demonstrating the central contribution of the circuit projecting from ventral hippocampus to nucleus accumbens and how inherent sex differences in the excitability of this circuit may predict and drive depression-related behaviors. The findings covered in this review underscore the continued need for studies using preclinical models and circuit-specific strategies for uncovering molecular and physiological mechanisms that could lead to potential sex-specific diagnosis, prognosis, prevention, and/or treatments for MDD and other mood disorders.
Keywords: Sex Differences in Brain and Behavior
PubDate: 2021-08-17T07:35:11-07:00
DOI: 10.1101/cshperspect.a039198
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- [Early Release Articles] Nuclear Compartments: An Incomplete Primer to
Nuclear Compartments, Bodies, and Genome Organization Relative to Nuclear
Architecture-
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Authors: Belmont; A. S.
Abstract: This work reviews nuclear compartments, defined broadly to include distinct nuclear structures, bodies, and chromosome domains. It first summarizes original cytological observations before comparing concepts of nuclear compartments emerging from microscopy versus genomic approaches and then introducing new multiplexed imaging approaches that promise in the future to meld both approaches. I discuss how previous models of radial distribution of chromosomes or the binary division of the genome into A and B compartments are now being refined by the recognition of more complex nuclear compartmentalization. The poorly understood question of how these nuclear compartments are established and maintained is then discussed, including through the modern perspective of phase separation, before moving on to address possible functions of nuclear compartments, using the possible role of nuclear speckles in modulating gene expression as an example. Finally, the review concludes with a discussion of future questions for this field.
Keywords: The Nucleus
PubDate: 2021-08-16T12:09:56-07:00
DOI: 10.1101/cshperspect.a041268
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- [Early Release Articles] Inducing Vertebrate Limb Regeneration: A Review
of Past Advances and Future Outlook-
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Authors: Davidian, D; Levin, M.
Abstract: Limb loss due to traumatic injury or amputation is a major biomedical burden. Many vertebrates exhibit the ability to form and pattern normal limbs during embryogenesis from amorphous clusters of precursor cells, hinting that this process could perhaps be activated later in life to rebuild missing or damaged limbs. Indeed, some animals, such as salamanders, are proficient regenerators of limbs throughout their life span. Thus, research over the last century has sought to stimulate regeneration in species that do not normally regenerate their appendages. Importantly, these efforts are not only a vital aspect of regenerative medicine, but also have fundamental implications for understanding evolution and the cellular control of growth and form throughout the body. Here we review major recent advances in augmenting limb regeneration, summarizing the degree of success that has been achieved to date in frog and mammalian models using genetic, biochemical, and bioelectrical interventions. While the degree of whole limb repair in rodent models has been modest to date, a number of new technologies and approaches comprise an exciting near-term road map for basic and clinical progress in regeneration.
Keywords: Regeneration
PubDate: 2021-08-16T12:09:56-07:00
DOI: 10.1101/cshperspect.a040782
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- [Early Release Articles] Fourteen Stations of Auxin
-
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Authors: Friml; J.
Abstract: Auxin has always been at the forefront of research in plant physiology and development. Since the earliest contemplations by Julius von Sachs and Charles Darwin, more than a century-long struggle has been waged to understand its function. This largely reflects the failures, successes, and inevitable progress in the entire field of plant signaling and development. Here I present 14 stations on our long and sometimes mystical journey to understand auxin. These highlights were selected to give a flavor of the field and to show the scope and limits of our current knowledge. A special focus is put on features that make auxin unique among phytohormones, such as its dynamic, directional transport network, which integrates external and internal signals, including self-organizing feedback. Accented are persistent mysteries and controversies. The unexpected discoveries related to rapid auxin responses and growth regulation recently disturbed our contentment regarding understanding of the auxin signaling mechanism. These new revelations, along with advances in technology, usher us into a new, exciting era in auxin research.
Keywords: Auxin Signaling
PubDate: 2021-08-16T12:09:56-07:00
DOI: 10.1101/cshperspect.a039859
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- [Early Release Articles] Essential Roles for RNA in Shaping Nuclear
Organization-
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Authors: Quinodoz, S. A; Guttman, M.
Abstract: It has long been proposed that nuclear RNAs might play an important role in organizing the structure of the nucleus. Initial experiments performed more than 30 years ago found that global disruption of RNA led to visible rearrangements of nuclear organization. Yet, this idea remained controversial for many years, in large part because it was unclear what specific RNAs might be involved, and which specific nuclear structures might be dependent on RNA. Over the past few years, the contributions of RNA to organizing nuclear structures have become clearer with the discovery that many nuclear bodies are enriched for specific noncoding RNAs (ncRNAs); in specific cases, ncRNAs have been shown to be essential for establishment and maintenance of these nuclear structures. More recently, many different ncRNAs have been shown to play critical roles in initiating the three-dimensional (3D) spatial organization of DNA, RNA, and protein molecules in the nucleus. These examples, combined with global imaging and genomic experiments, have begun to paint a picture of a broader role for RNA in nuclear organization and to uncover a unifying mechanism that may explain why RNA is a uniquely suited molecule for this role. In this review, we provide an overview of the history of RNA and nuclear structure and discuss key examples of RNA-mediated bodies, the global roles of ncRNAs in shaping nuclear structure, and emerging insights into mechanisms of RNA-mediated nuclear organization.
Keywords: The Nucleus
PubDate: 2021-08-16T12:09:56-07:00
DOI: 10.1101/cshperspect.a039719
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- [Early Release Articles] Uncovering the Principles of Genome Folding by 3D
Chromatin Modeling-
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Authors: Yildirim, A; Boninsegna, L, Zhan, Y, Alber, F.
Abstract: Our understanding of how genomic DNA is tightly packed inside the nucleus, yet is still accessible for vital cellular processes, has grown dramatically over recent years with advances in microscopy and genomics technologies. Computational methods have played a pivotal role in the structural interpretation of experimental data, which helped unravel some organizational principles of genome folding. Here, we give an overview of current computational efforts in mechanistic and data-driven 3D chromatin structure modeling. We discuss strengths and limitations of different methods and evaluate the added value and benefits of computational approaches to infer the 3D structural and dynamic properties of the genome and its underlying mechanisms at different scales and resolution, ranging from the dynamic formation of chromatin loops and topological associated domains to nuclear compartmentalization of chromatin and nuclear bodies.
Keywords: The Nucleus
PubDate: 2021-08-16T12:09:56-07:00
DOI: 10.1101/cshperspect.a039693
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- [Early Release Articles] Epigenetic Reprogramming in Early Animal
Development-
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Authors: Du, Z; Zhang, K, Xie, W.
Abstract: Dramatic nuclear reorganization occurs during early development to convert terminally differentiated gametes to a totipotent zygote, which then gives rise to an embryo. Aberrant epigenome resetting severely impairs embryo development and even leads to lethality. How the epigenomes are inherited, reprogrammed, and reestablished in this critical developmental period has gradually been unveiled through the rapid development of technologies including ultrasensitive chromatin analysis methods. In this review, we summarize the latest findings on epigenetic reprogramming in gametogenesis and embryogenesis, and how it contributes to gamete maturation and parental-to-zygotic transition. Finally, we highlight the key questions that remain to be answered to fully understand chromatin regulation and nuclear reprogramming in early development.
Keywords: The Nucleus
PubDate: 2021-08-16T12:09:56-07:00
DOI: 10.1101/cshperspect.a039677
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- [Early Release Articles] Structure, Maintenance, and Regulation of Nuclear
Pore Complexes: The Gatekeepers of the Eukaryotic Genome-
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Authors: Raices, M; D'Angelo, M. A.
Abstract: In eukaryotic cells, the genetic material is segregated inside the nucleus. This compartmentalization of the genome requires a transport system that allows cells to move molecules across the nuclear envelope, the membrane-based barrier that surrounds the chromosomes. Nuclear pore complexes (NPCs) are the central component of the nuclear transport machinery. These large protein channels penetrate the nuclear envelope, creating a passage between the nucleus and the cytoplasm through which nucleocytoplasmic molecule exchange occurs. NPCs are one of the largest protein assemblies of eukaryotic cells and, in addition to their critical function in nuclear transport, these structures also play key roles in many cellular processes in a transport-independent manner. Here we will review the current knowledge of the NPC structure, the cellular mechanisms that regulate their formation and maintenance, and we will provide a brief description of a variety of processes that NPCs regulate.
Keywords: The Nucleus
PubDate: 2021-07-26T11:14:26-07:00
DOI: 10.1101/cshperspect.a040691
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- [Early Release Articles] The Molecular and Nuclear Dynamics of
X-Chromosome Inactivation-
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Authors: Dossin, F; Heard, E.
Abstract: In female eutherian mammals, dosage compensation of X-linked gene expression is achieved during development through transcriptional silencing of one of the two X chromosomes. Following X chromosome inactivation (XCI), the inactive X chromosome remains faithfully silenced throughout somatic cell divisions. XCI is dependent on Xist, a long noncoding RNA that coats and silences the X chromosome from which it is transcribed. Xist coating triggers a cascade of chromosome-wide changes occurring at the levels of transcription, chromatin composition, chromosome structure, and spatial organization within the nucleus. XCI has emerged as a paradigm for the study of such crucial nuclear processes and the dissection of their functional interplay. In the past decade, the advent of tools to characterize and perturb these processes have provided an unprecedented understanding into their roles during XCI. The mechanisms orchestrating the initiation of XCI as well as its maintenance are thus being unraveled, although many questions still remain. Here, we introduce key aspects of the XCI process and review the recent discoveries about its molecular basis.
Keywords: The Nucleus
PubDate: 2021-07-26T11:14:26-07:00
DOI: 10.1101/cshperspect.a040196
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- [Early Release Articles] 3D or Not 3D: Shaping the Genome during
Development-
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Authors: Glaser, J; Mundlos, S.
Abstract: One of the most fundamental questions in developmental biology is how one fertilized cell can give rise to a fully mature organism and how gene regulation governs this process. Precise spatiotemporal gene expression is required for development and is believed to be achieved through a complex interplay of sequence-specific information, epigenetic modifications, trans-acting factors, and chromatin folding. Here we review the role of chromatin folding during development, the mechanisms governing 3D genome organization, and how it is established in the embryo. Furthermore, we discuss recent advances and debated questions regarding the contribution of the 3D genome to gene regulation during organogenesis. Finally, we describe the mechanisms that can reshape the 3D genome, including disease-causing structural variations and the emerging view that transposable elements contribute to chromatin organization.
Keywords: The Nucleus
PubDate: 2021-07-26T11:14:26-07:00
DOI: 10.1101/cshperspect.a040188
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- [Early Release Articles] Auxin in Root Development
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Authors: Roychoudhry, S; Kepinski, S.
Abstract: Root system architecture is an important determinant of below-ground resource capture and hence overall plant fitness. The plant hormone auxin plays a central role in almost every facet of root development from the cellular to the whole-root-system level. Here, using Arabidopsis as a model, we review the multiple gene signaling networks regulated by auxin biosynthesis, conjugation, and transport that underpin primary and lateral root development. We describe the role of auxin in establishing the root apical meristem and discuss how the tight spatiotemporal regulation of auxin distribution controls transitions between cell division, cell growth, and differentiation. This includes the localized reestablishment of mitotic activity required to elaborate the root system via the production of lateral roots. We also summarize recent discoveries on the effects of auxin and auxin signaling and transport on the control of lateral root gravitropic setpoint angle (GSA), a critical determinant of the overall shape of the root system. Finally, we discuss how environmental conditions influence root developmental plasticity by modulation of auxin biosynthesis, transport, and the canonical auxin signaling pathway.
Keywords: Auxin Signaling
PubDate: 2021-07-26T11:14:26-07:00
DOI: 10.1101/cshperspect.a039933
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- [Early Release Articles] The Impact of Space and Time on the Functional
Output of the Genome-
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Authors: Nollmann, M; Bennabi, I, Götz, M, Gregor, T.
Abstract: Over the past two decades, it has become clear that the multiscale spatial and temporal organization of the genome has important implications for nuclear function. This review centers on insights gained from recent advances in light microscopy on our understanding of transcription. We discuss spatial and temporal aspects that shape nuclear order and their consequences on regulatory components, focusing on genomic scales most relevant to function. The emerging picture is that spatiotemporal constraints increase the complexity in transcriptional regulation, highlighting new challenges, such as uncertainty about how information travels from molecular factors through the genome and space to generate a functional output.
Keywords: The Nucleus
PubDate: 2021-07-06T10:16:33-07:00
DOI: 10.1101/cshperspect.a040378
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- [Early Release Articles] Chromatin Mechanisms Driving Cancer
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Authors: Gryder, B; Scacheri, P. C, Ried, T, Khan, J.
Abstract: The change in cell state from normal to malignant is driven fundamentally by oncogenic mutations in cooperation with epigenetic alterations of chromatin. These alterations in chromatin can be a consequence of environmental stressors or germline and/or somatic mutations that directly alter the structure of chromatin machinery proteins, their levels, or their regulatory function. These changes can result in an inability of the cell to differentiate along a predefined lineage path, or drive a hyperactive, highly proliferative state with addiction to high levels of transcriptional output. We discuss how these genetic alterations hijack the chromatin machinery for the oncogenic process to reveal unique vulnerabilities and novel targets for cancer therapy.
Keywords: The Nucleus
PubDate: 2021-06-29T08:07:41-07:00
DOI: 10.1101/cshperspect.a040956
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- [Early Release Articles] Defining the Molecular Hallmarks of T-Cell Memory
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Authors: Zebley, C. C; Akondy, R. S, Youngblood, B. A, Kissick, H. T.
Abstract: The pool of memory CD8 T cells is comprised of highly specialized subpopulations of cells with both shared and distinct functions. The ongoing study of T-cell memory is focused on how these different subpopulations arise, how the cells are maintained over the life of the host, and how the cells protect a host against reinfection. As a field we have used the convenience of a narrow range of surface markers to define and study these memory T-cell subsets. However, as we learn more about these cells, it is becoming clear that these broad definitions are insufficient to capture the complexity of the CD8 memory T-cell pool, and an updated definition of these cellular states are needed. Here, we discuss data that have recently arisen that highlight the difficulty in using surface markers to functionally characterize CD8 T-cell populations, and the possibility of using the epigenetic state of cells to more clearly define the functional capacity of CD8 memory T-cell subsets.
Keywords: T-Cell Memory
PubDate: 2021-06-14T12:08:21-07:00
DOI: 10.1101/cshperspect.a037804
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- [Early Release Articles] Computational Models of Auxin-Driven Patterning
in Shoots-
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Authors: Cieslak, M; Owens, A, Prusinkiewicz, P.
Abstract: Auxin regulates many aspects of plant development and behavior, including the initiation of new outgrowth, patterning of vascular systems, control of branching, and responses to the environment. Computational models have complemented experimental studies of these processes. We review these models from two perspectives. First, we consider cellular and tissue-level models of interaction between auxin and its transporters in shoots. These models form a coherent body of results exploring different hypotheses pertinent to the patterning of new outgrowth and vascular strands. Second, we consider models operating at the level of plant organs and entire plants. We highlight techniques used to reduce the complexity of these models, which provide a path to capturing the essence of studied phenomena while running simulations efficiently.
Keywords: Auxin Signaling
PubDate: 2021-05-17T09:06:31-07:00
DOI: 10.1101/cshperspect.a040097
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