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Journal Cover Journal of Developmental Biology
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  This is an Open Access Journal Open Access journal
   ISSN (Online) 2221-3759
   Published by MDPI Homepage  [148 journals]
  • JDB, Vol. 5, Pages 1: Acknowledgement to Reviewers of Journal of
           Developmental Biology in 2016

    • Authors: JDB Editorial Office
      First page: 1
      Abstract: n/a
      PubDate: 2017-01-11
      DOI: 10.3390/jdb5010001
      Issue No: Vol. 5, No. 1 (2017)
  • JDB, Vol. 5, Pages 2: Sonic Hedgehog—‘Jack-of-All-Trades’ in Neural
           Circuit Formation

    • Authors: Nikole Zuñiga, Esther Stoeckli
      First page: 2
      Abstract: As reflected by the term morphogen, molecules such as Shh and Wnts were identified based on their role in early development when they instruct precursor cells to adopt a specific cell fate. Only much later were they implicated in neural circuit formation. Both in vitro and in vivo studies indicated that morphogens direct axons during their navigation through the developing nervous system. Today, the best understood role of Shh and Wnt in axon guidance is their effect on commissural axons in the spinal cord. Shh was shown to affect commissural axons both directly and indirectly via its effect on Wnt signaling. In fact, throughout neural circuit formation there is cross-talk and collaboration of Shh and Wnt signaling. Thus, although the focus of this review is on the role of Shh in neural circuit formation, a separation from Wnt signaling is not possible.
      PubDate: 2017-02-08
      DOI: 10.3390/jdb5010002
      Issue No: Vol. 5, No. 1 (2017)
  • JDB, Vol. 4, Pages 29: Loss of Suppressor of Fused Mid-Corticogenesis
           Leads to the Expansion of Intermediate Progenitors

    • Authors: Odessa Yabut, Hui Ng, Gloria Fernandez, Keejung Yoon, Jeremy Kuhn, Samuel Pleasure
      First page: 29
      Abstract: Neural progenitors in the embryonic neocortex must be tightly regulated in order to generate the correct number and projection neuron subtypes necessary for the formation of functional neocortical circuits. In this study, we show that the intracellular protein Suppressor of Fused (Sufu) regulates the proliferation of intermediate progenitor (IP) cells at later stages of corticogenesis to affect the number of Cux1+ upper layer neurons in the postnatal neocortex. This correlates with abnormal levels of the repressor form of Gli3 (Gli3R) and the ectopic expression of Patched 1 (Ptch1), a Sonic Hedgehog (Shh) target gene. These studies reveal that the canonical role of Sufu as an inhibitor of Shh signaling is conserved at later stages of corticogenesis and that Sufu plays a crucial role in regulating neuronal number by controlling the cell cycle dynamics of IP cells in the embryonic neocortex.
      PubDate: 2016-09-29
      DOI: 10.3390/jdb4040029
      Issue No: Vol. 4, No. 4 (2016)
  • JDB, Vol. 4, Pages 30: Hedgehog Signaling in Prostate Development,
           Regeneration and Cancer

    • Authors: Wade Bushman
      First page: 30
      Abstract: The prostate is a developmental model system study of prostate growth regulation. Historically the research focus was on androgen regulation of development and growth and instructive interactions between the mesenchyme and epithelium. The study of Hh signaling in prostate development revealed important roles in ductal morphogenesis and in epithelial growth regulation that appear to be recapitulated in prostate cancer. This overview of Hh signaling in the prostate will address the well-described role of paracrine signaling prostate development as well as new evidence suggesting a role for autocrine signaling, the role of Hh signaling in prostate regeneration and reiterative activities in prostate cancer.
      PubDate: 2016-10-19
      DOI: 10.3390/jdb4040030
      Issue No: Vol. 4, No. 4 (2016)
  • JDB, Vol. 4, Pages 31: An Evolutionarily Conserved Network Mediates
           Development of the zona limitans intrathalamica, a Sonic
           Hedgehog-Secreting Caudal Forebrain Signaling Center

    • Authors: Elena Sena, Kerstin Feistel, Béatrice Durand
      First page: 31
      Abstract: Recent studies revealed new insights into the development of a unique caudal forebrain-signaling center: the zona limitans intrathalamica (zli). The zli is the last brain signaling center to form and the first forebrain compartment to be established. It is the only part of the dorsal neural tube expressing the morphogen Sonic Hedgehog (Shh) whose activity participates in the survival, growth and patterning of neuronal progenitor subpopulations within the thalamic complex. Here, we review the gene regulatory network of transcription factors and cis-regulatory elements that underlies formation of a shh-expressing delimitated domain in the anterior brain. We discuss evidence that this network predates the origin of chordates. We highlight the contribution of Shh, Wnt and Notch signaling to zli development and discuss implications for the fact that the morphogen Shh relies on primary cilia for signal transduction. The network that underlies zli development also contributes to thalamus induction, and to its patterning once the zli has been set up. We present an overview of the brain malformations possibly associated with developmental defects in this gene regulatory network (GRN).
      PubDate: 2016-10-20
      DOI: 10.3390/jdb4040031
      Issue No: Vol. 4, No. 4 (2016)
  • JDB, Vol. 4, Pages 32: Asxl2−/− Mice Exhibit De Novo Cardiomyocyte
           Production during Adulthood

    • Authors: Rachel Brunner, Hsiao-Lei Lai, Zane Deliu, Elan Melman, David Geenen, Q. Wang
      First page: 32
      Abstract: Heart attacks affect more than seven million people worldwide each year. A heart attack, or myocardial infarction, may result in the death of a billion cardiomyocytes within hours. The adult mammalian heart does not have an effective mechanism to replace lost cardiomyocytes. Instead, lost muscle is replaced with scar tissue, which decreases blood pumping ability and leads to heart failure over time. Here, we report that the loss of the chromatin factor ASXL2 results in spontaneous proliferation and cardiogenic differentiation of a subset of interstitial non-cardiomyocytes. The adult Asxl2−/− heart displays spontaneous overgrowth without cardiomyocyte hypertrophy. Thymidine analog labeling and Ki67 staining of 12-week-old hearts revealed 3- and 5-fold increases of proliferation rate for vimentin+ non-cardiomyocytes in Asxl2−/− over age- and sex-matched wildtype controls, respectively. Approximately 10% of proliferating non-cardiomyocytes in the Asxl2−/− heart express the cardiogenic marker NKX2-5, a frequency that is ~7-fold higher than that observed in the wildtype. EdU lineage tracing experiments showed that ~6% of pulsed-labeled non-cardiomyocytes in Asxl2−/− hearts differentiate into mature cardiomyocytes after a four-week chase, a phenomenon not observed for similarly pulse-chased wildtype controls. Taken together, these data indicate de novo cardiomyocyte production in the Asxl2−/− heart due to activation of a population of proliferative cardiogenic non-cardiomyocytes. Our study suggests the existence of an epigenetic barrier to cardiogenicity in the adult heart and raises the intriguing possibility of unlocking regenerative potential via transient modulation of epigenetic activity.
      PubDate: 2016-11-03
      DOI: 10.3390/jdb4040032
      Issue No: Vol. 4, No. 4 (2016)
  • JDB, Vol. 4, Pages 33: Yeast Gup1(2) Proteins Are Homologues of the
           Hedgehog Morphogens Acyltransferases HHAT(L): Facts and Implications

    • Authors: Cândida Lucas, Célia Ferreira, Giulia Cazzanelli, Ricardo Franco-Duarte, Joana Tulha
      First page: 33
      Abstract: In multiple tissues, the Hedgehog secreted morphogen activates in the receiving cells a pathway involved in cell fate, proliferation and differentiation in the receiving cells. This pathway is particularly important during embryogenesis. The protein HHAT (Hedgehog O-acyltransferase) modifies Hh morphogens prior to their secretion, while HHATL (Hh O-acyltransferase-like) negatively regulates the pathway. HHAT and HHATL are homologous to Saccharomyces cerevisiae Gup2 and Gup1, respectively. In yeast, Gup1 is associated with a high number and diversity of biological functions, namely polarity establishment, secretory/endocytic pathway functionality, vacuole morphology and wall and membrane composition, structure and maintenance. Phenotypes underlying death, morphogenesis and differentiation are also included. Paracrine signalling, like the one promoted by the Hh pathway, has not been shown to occur in microbial communities, despite the fact that large aggregates of cells like biofilms or colonies behave as proto-tissues. Instead, these have been suggested to sense the population density through the secretion of quorum-sensing chemicals. This review focuses on Gup1/HHATL and Gup2/HHAT proteins. We review the functions and physiology associated with these proteins in yeasts and higher eukaryotes. We suggest standardisation of the presently chaotic Gup-related nomenclature, which includes KIAA117, c3orf3, RASP, Skinny, Sightless and Central Missing, in order to avoid the disclosure of otherwise unnoticed information.
      PubDate: 2016-11-05
      DOI: 10.3390/jdb4040033
      Issue No: Vol. 4, No. 4 (2016)
  • JDB, Vol. 4, Pages 34: Perspectives on Intra- and Intercellular
           Trafficking of Hedgehog for Tissue Patterning

    • Authors: Eléanor Simon, Adrián Aguirre-Tamaral, Gustavo Aguilar, Isabel Guerrero
      First page: 34
      Abstract: Intercellular communication is a fundamental process for correct tissue development. The mechanism of this process involves, among other things, the production and secretion of signaling molecules by specialized cell types and the capability of these signals to reach the target cells in order to trigger specific responses. Hedgehog (Hh) is one of the best-studied signaling pathways because of its importance during morphogenesis in many organisms. The Hh protein acts as a morphogen, activating its targets at a distance in a concentration-dependent manner. Post-translational modifications of Hh lead to a molecule covalently bond to two lipid moieties. These lipid modifications confer Hh high affinity to lipidic membranes, and intense studies have been carried out to explain its release into the extracellular matrix. This work reviews Hh molecule maturation, the intracellular recycling needed for its secretion and the proposed carriers to explain Hh transportation to the receiving cells. Special focus is placed on the role of specialized filopodia, also named cytonemes, in morphogen transport and gradient formation.
      PubDate: 2016-12-02
      DOI: 10.3390/jdb4040034
      Issue No: Vol. 4, No. 4 (2016)
  • JDB, Vol. 4, Pages 35: The Many Hats of Sonic Hedgehog Signaling in
           Nervous System Development and Disease

    • Authors: Yesser Belgacem, Andrew Hamilton, Sangwoo Shim, Kira Spencer, Laura Borodinsky
      First page: 35
      Abstract: Sonic hedgehog (Shh) signaling occurs concurrently with the many processes that constitute nervous system development. Although Shh is mostly known for its proliferative and morphogenic action through its effects on neural stem cells and progenitors, it also contributes to neuronal differentiation, axonal pathfinding and synapse formation and function. To participate in these diverse events, Shh signaling manifests differently depending on the maturational state of the responsive cell, on the other signaling pathways regulating neural cell function and the environmental cues that surround target cells. Shh signaling is particularly dynamic in the nervous system, ranging from canonical transcription-dependent, to non-canonical and localized to axonal growth cones. Here, we review the variety of Shh functions in the developing nervous system and their consequences for neurodevelopmental diseases and neural regeneration, with particular emphasis on the signaling mechanisms underlying Shh action.
      PubDate: 2016-12-10
      DOI: 10.3390/jdb4040035
      Issue No: Vol. 4, No. 4 (2016)
  • JDB, Vol. 4, Pages 36: Differential Cellular Responses to Hedgehog
           Signalling in Vertebrates—What is the Role of Competence'

    • Authors: Clemens Kiecker, Anthony Graham, Malcolm Logan
      First page: 36
      Abstract: A surprisingly small number of signalling pathways generate a plethora of cellular responses ranging from the acquisition of multiple cell fates to proliferation, differentiation, morphogenesis and cell death. These diverse responses may be due to the dose-dependent activities of signalling factors, or to intrinsic differences in the response of cells to a given signal—a phenomenon called differential cellular competence. In this review, we focus on temporal and spatial differences in competence for Hedgehog (HH) signalling, a signalling pathway that is reiteratively employed in embryos and adult organisms. We discuss the upstream signals and mechanisms that may establish differential competence for HHs in a range of different tissues. We argue that the changing competence for HH signalling provides a four-dimensional framework for the interpretation of the signal that is essential for the emergence of functional anatomy. A number of diseases—including several types of cancer—are caused by malfunctions of the HH pathway. A better understanding of what provides differential competence for this signal may reveal HH-related disease mechanisms and equip us with more specific tools to manipulate HH signalling in the clinic.
      PubDate: 2016-12-10
      DOI: 10.3390/jdb4040036
      Issue No: Vol. 4, No. 4 (2016)
  • JDB, Vol. 4, Pages 22: Hedgehog Signalling in the Embryonic Mouse Thymus

    • Authors: Alessandro Barbarulo, Ching-In Lau, Konstantinos Mengrelis, Susan Ross, Anisha Solanki, José Saldaña, Tessa Crompton
      First page: 22
      Abstract: T cells develop in the thymus, which provides an essential environment for T cell fate specification, and for the differentiation of multipotent progenitor cells into major histocompatibility complex (MHC)-restricted, non-autoreactive T cells. Here we review the role of the Hedgehog signalling pathway in T cell development, thymic epithelial cell (TEC) development, and thymocyte–TEC cross-talk in the embryonic mouse thymus during the last week of gestation.
      PubDate: 2016-07-16
      DOI: 10.3390/jdb4030022
      Issue No: Vol. 4, No. 3 (2016)
  • JDB, Vol. 4, Pages 23: Regulation of Hedgehog Signalling Inside and
           Outside the Cell

    • Authors: Simon Ramsbottom, Mary Pownall
      First page: 23
      Abstract: The hedgehog (Hh) signalling pathway is conserved throughout metazoans and plays an important regulatory role in both embryonic development and adult homeostasis. Many levels of regulation exist that control the release, reception, and interpretation of the hedgehog signal. The fatty nature of the Shh ligand means that it tends to associate tightly with the cell membrane, and yet it is known to act as a morphogen that diffuses to elicit pattern formation. Heparan sulfate proteoglycans (HSPGs) play a major role in the regulation of Hh distribution outside the cell. Inside the cell, the primary cilium provides an important hub for processing the Hh signal in vertebrates. This review will summarise the current understanding of how the Hh pathway is regulated from ligand production, release, and diffusion, through to signal reception and intracellular transduction.
      PubDate: 2016-07-20
      DOI: 10.3390/jdb4030023
      Issue No: Vol. 4, No. 3 (2016)
  • JDB, Vol. 4, Pages 24: The Role of Sonic Hedgehog in Craniofacial
           Patterning, Morphogenesis and Cranial Neural Crest Survival

    • Authors: Sebastian Dworkin, Yeliz Boglev, Harley Owens, Stephen Goldie
      First page: 24
      Abstract: Craniofacial defects (CFD) are a significant healthcare problem worldwide. Understanding both the morphogenetic movements which underpin normal facial development, as well as the molecular factors which regulate these processes, forms the cornerstone of future diagnostic, and ultimately, preventative therapies. The soluble morphogen Sonic hedgehog (Shh), a vertebrate orthologue of Drosophila hedgehog, is a key signalling factor in the regulation of craniofacial skeleton development in vertebrates, operating within numerous tissue types in the craniofacial primordia to spatiotemporally regulate the formation of the face and jaws. This review will provide an overview of normal craniofacial skeleton development, and focus specifically on the known roles of Shh in regulating the development and progression of the first pharyngeal arch, which in turn gives rise to both the upper jaw (maxilla) and lower jaw (mandible).
      PubDate: 2016-08-03
      DOI: 10.3390/jdb4030024
      Issue No: Vol. 4, No. 3 (2016)
  • JDB, Vol. 4, Pages 25: A Joint Less Ordinary: Intriguing Roles for
           Hedgehog Signalling in the Development of the Temporomandibular Synovial

    • Authors: Malgorzata Kubiak, Mark Ditzel
      First page: 25
      Abstract: This review highlights the essential role of Hedgehog (Hh) signalling in the developmental steps of temporomandibular joint (TMJ) formation. We review evidence for intra- and potentially inter-tissue Hh signaling as well as Glioma-Associated Oncogene Homolog (GLI) dependent and independent functions. Morphogenesis and maturation of the TMJ’s individual components and the general landscape of Hh signalling is also covered. Comparison of the appendicular knee and axial TMJ also reveals interesting differences and similarities in their mechanisms of development, chondrogenesis and reliance on Hh signalling.
      PubDate: 2016-08-26
      DOI: 10.3390/jdb4030025
      Issue No: Vol. 4, No. 3 (2016)
  • JDB, Vol. 4, Pages 26: Hedgehog Promotes Production of Inhibitory
           Interneurons in Vivo and in Vitro from Pluripotent Stem Cells

    • Authors: Nickesha Anderson, Christopher Chen, Laura Grabel
      First page: 26
      Abstract: Loss or damage of cortical inhibitory interneurons characterizes a number of neurological disorders. There is therefore a great deal of interest in learning how to generate these neurons from a pluripotent stem cell source so they can be used for cell replacement therapies or for in vitro drug testing. To design a directed differentiation protocol, a number of groups have used the information gained in the last 15 years detailing the conditions that promote interneuron progenitor differentiation in the ventral telencephalon during embryogenesis. The use of Hedgehog peptides and agonists is featured prominently in these approaches. We review here the data documenting a role for Hedgehog in specifying interneurons in both the embryonic brain during development and in vitro during the directed differentiation of pluripotent stem cells.
      PubDate: 2016-08-26
      DOI: 10.3390/jdb4030026
      Issue No: Vol. 4, No. 3 (2016)
  • JDB, Vol. 4, Pages 27: Control of Hedgehog Signalling by the
           Cilia-Regulated Proteasome

    • Authors: Christoph Gerhardt, Antonia Wiegering, Tristan Leu, Ulrich Rüther
      First page: 27
      Abstract: The Hedgehog signalling pathway is evolutionarily highly conserved and essential for embryonic development of invertebrates and vertebrates. Consequently, impaired Hedgehog signalling results in very severe human diseases, ranging from holoprosencephaly to Pallister-Hall syndrome. Due to this great importance for human health, the focus of numerous research groups is placed on the investigation of the detailed mechanisms underlying Hedgehog signalling. Today, it is known that tiny cell protrusions, known as primary cilia, are necessary to mediate Hedgehog signalling in vertebrates. Although the Hedgehog pathway is one of the best studied signalling pathways, many questions remain. One of these questions is: How do primary cilia control Hedgehog signalling in vertebrates' Recently, it was shown that primary cilia regulate a special kind of proteasome which is essential for proper Hedgehog signalling. This review article will cover this novel cilia-proteasome association in embryonic Hedgehog signalling and discuss the possibilities provided by future investigations on this topic.
      PubDate: 2016-09-03
      DOI: 10.3390/jdb4030027
      Issue No: Vol. 4, No. 3 (2016)
  • JDB, Vol. 4, Pages 28: Hedgehog: A Key Signaling in the Development of the
           Oligodendrocyte Lineage

    • Authors: Elisabeth Traiffort, Mary Zakaria, Yousra Laouarem, Julien Ferent
      First page: 28
      Abstract: The Hedgehog morphogen aroused an enormous interest since it was characterized as an essential signal for ventral patterning of the spinal cord two decades ago. The pathway is notably implicated in the initial appearance of the progenitors of oligodendrocytes (OPCs), the glial cells of the central nervous system which after maturation are responsible for axon myelination. In accordance with the requirement for Hedgehog signaling in ventral patterning, the earliest identifiable cells in the oligodendrocyte lineage are derived from the ventral ventricular zone of the developing spinal cord and brain. Here, we present the current knowledge about the involvement of Hedgehog signaling in the strict spatial and temporal regulation which characterizes the initiation and progression of the oligodendrocyte lineage. We notably describe the ability of the Hedgehog signaling to tightly orchestrate the appearance of specific combinations of genes in concert with other pathways. We document the molecular mechanisms controlling Hedgehog temporal activity during OPC specification. The contribution of the pathway to aspects of OPC development different from their specification is also highlighted especially in the optic nerve. Finally, we report the data demonstrating that Hedgehog signaling-dependency is not a universal situation for oligodendrocyte generation as evidenced in the dorsal spinal cord in contrast to the dorsal forebrain.
      PubDate: 2016-09-08
      DOI: 10.3390/jdb4030028
      Issue No: Vol. 4, No. 3 (2016)
  • JDB, Vol. 4, Pages 13: Hoxa5: A Key Player in Development and Disease

    • Authors: Lucie Jeannotte, Florian Gotti, Kim Landry-Truchon
      First page: 13
      Abstract: A critical position in the developmental hierarchy is occupied by the Hox genes, which encode transcription factors. Hox genes are crucial in specifying regional identity along the embryonic axes and in regulating morphogenesis. In mouse, targeted mutations of Hox genes cause skeletal transformations and organ defects that can impair viability. Here, we present the current knowledge about the Hoxa5 gene, a paradigm for the function and the regulation of Hox genes. The phenotypic survey of Hoxa5−/− mice has unveiled its critical role in the regional specification of the skeleton and in organogenesis. Most Hoxa5−/− mice die at birth from respiratory distress due to tracheal and lung dysmorphogenesis and impaired diaphragm innervation. The severity of the phenotype establishes that Hoxa5 plays a predominant role in lung organogenesis versus other Hox genes. Hoxa5 also governs digestive tract morphogenesis, thyroid and mammary glands development, and ovary homeostasis. Deregulated Hoxa5 expression is reported in cancers, indicating Hoxa5 involvement in tumor predisposition and progression. The dynamic Hoxa5 expression profile is under the transcriptional control of multiple cis-acting sequences and trans-acting regulators. It is also modulated by epigenetic mechanisms, implicating chromatin modifications and microRNAs. Finally, lncRNAs originating from alternative splicing and distal promoters encompass the Hoxa5 locus.
      PubDate: 2016-03-25
      DOI: 10.3390/jdb4020013
      Issue No: Vol. 4, No. 2 (2016)
  • JDB, Vol. 4, Pages 14: Hox Genes in Cardiovascular Development and

    • Authors: Marine Roux, Stéphane Zaffran
      First page: 14
      Abstract: Congenital heart defects (CHD) are the leading cause of death in the first year of life. Over the past 20 years, much effort has been focused on unraveling the genetic bases of CHD. In particular, studies in human genetics coupled with those of model organisms have provided valuable insights into the gene regulatory networks underlying CHD pathogenesis. Hox genes encode transcription factors that are required for the patterning of the anterior–posterior axis in the embryo. In this review, we focus on the emerging role of anteriorly expressed Hox genes (Hoxa1, Hoxb1, and Hoxa3) in cardiac development, specifically their contribution to patterning of cardiac progenitor cells and formation of the great arteries. Recent evidence regarding the cooperative regulation of heart development by Hox proteins with members of the TALE-class of homeodomain proteins such as Pbx and Meis transcription factors is also discussed. These findings are highly relevant to human pathologies as they pinpoint new genes that increase susceptibility to cardiac anomalies and provide novel mechanistic insights into CHD.
      PubDate: 2016-03-24
      DOI: 10.3390/jdb4020014
      Issue No: Vol. 4, No. 2 (2016)
  • JDB, Vol. 4, Pages 15: Functional and Comparative Genomics of Hoxa2 Gene
           cis-Regulatory Elements: Evidence for Evolutionary Modification of
           Ancestral Core Element Activity

    • Authors: Adam Davis, Michael Reubens, Edmund Stellwag
      First page: 15
      Abstract: Hoxa2 is an evolutionarily conserved developmental regulatory gene that functions to specify rhombomere (r) and pharyngeal arch (PA) identities throughout the Osteichthyes. Japanese medaka (Oryzias latipes) hoxa2a, like orthologous Hoxa2 genes from other osteichthyans, is expressed during embryogenesis in r2–7 and PA2-7, whereas the paralogous medaka pseudogene, ψhoxa2b, is expressed in noncanonical Hoxa2 domains, including the pectoral fin buds. To understand the evolution of cis-regulatory element (CRE) control of gene expression, we conducted eGFP reporter gene expression studies with extensive functional mapping of several conserved CREs upstream of medaka hoxa2a and ψhoxa2b in transient and stable-line transgenic medaka embryos. The CREs tested were previously shown to contribute to directing mouse Hoxa2 gene expression in r3, r5, and PA2-4. Our results reveal the presence of sequence elements embedded in the medaka hoxa2a and ψhoxa2b upstream enhancer regions (UERs) that mediate expression in r4 and the PAs (hoxa2a r4/CNCC element) or in r3–7 and the PAs ψhoxa2b r3–7/CNCC element), respectively. Further, these elements were shown to be highly conserved among osteichthyans, which suggests that the r4 specifying element embedded in the UER of Hoxa2 is a deeply rooted rhombomere specifying element and the activity of this element has been modified by the evolution of flanking sequences that redirect its activity to alternative developmental compartments.
      PubDate: 2016-03-26
      DOI: 10.3390/jdb4020015
      Issue No: Vol. 4, No. 2 (2016)
  • JDB, Vol. 4, Pages 16: Mechanisms of Specificity for Hox Factor Activity

    • Authors: Arya Zandvakili, Brian Gebelein
      First page: 16
      Abstract: Metazoans encode clusters of paralogous Hox genes that are critical for proper development of the body plan. However, there are a number of unresolved issues regarding how paralogous Hox factors achieve specificity to control distinct cell fates. First, how do Hox paralogs, which have very similar DNA binding preferences in vitro, drive different transcriptional programs in vivo' Second, the number of potential Hox binding sites within the genome is vast compared to the number of sites bound. Hence, what determines where in the genome Hox factors bind' Third, what determines whether a Hox factor will activate or repress a specific target gene' Here, we review the current evidence that is beginning to shed light onto these questions. In particular, we highlight how cooperative interactions with other transcription factors (especially PBC and HMP proteins) and the sequences of cis-regulatory modules provide a basis for the mechanisms of Hox specificity. We conclude by integrating a number of the concepts described throughout the review in a case study of a highly interrogated Drosophila cis-regulatory module named “The Distal-less Conserved Regulatory Element” (DCRE).
      PubDate: 2016-05-09
      DOI: 10.3390/jdb4020016
      Issue No: Vol. 4, No. 2 (2016)
  • JDB, Vol. 4, Pages 17: Nutrient-Deprived Retinal Progenitors Proliferate
           in Response to Hypoxia: Interaction of the HIF-1 and mTOR Pathway

    • Authors: Helena Khaliullina, Nicola Love, William Harris
      First page: 17
      Abstract: At a cellular level, nutrients are sensed by the mechanistic Target of Rapamycin (mTOR). The response of cells to hypoxia is regulated via action of the oxygen sensor Hypoxia-Inducible Factor 1 (HIF-1). During development, injury and disease, tissues might face conditions of both low nutrient supply and low oxygen, yet it is not clear how cells adapt to both nutrient restriction and hypoxia, or how mTOR and HIF-1 interact in such conditions. Here we explore this question in vivo with respect to cell proliferation using the ciliary marginal zone (CMZ) of Xenopus. We found that both nutrient-deprivation and hypoxia cause retinal progenitors to decrease their proliferation, yet when nutrient-deprived progenitors are exposed to hypoxia there is an unexpected rise in cell proliferation. This increase, mediated by HIF-1 signalling, is dependent on glutaminolysis and reactivation of the mTOR pathway. We discuss how these findings in non-transformed tissue may also shed light on the ability of cancer cells in poorly vascularised solid tumours to proliferate.
      PubDate: 2016-05-19
      DOI: 10.3390/jdb4020017
      Issue No: Vol. 4, No. 2 (2016)
  • JDB, Vol. 4, Pages 18: Developmental Mechanism of Limb Field Specification
           along the Anterior–Posterior Axis during Vertebrate Evolution

    • Authors: Mikiko Tanaka
      First page: 18
      Abstract: In gnathostomes, limb buds arise from the lateral plate mesoderm at discrete positions along the body axis. Specification of these limb-forming fields can be subdivided into several steps. The lateral plate mesoderm is regionalized into the anterior lateral plate mesoderm (ALPM; cardiac mesoderm) and the posterior lateral plate mesoderm (PLPM). Subsequently, Hox genes appear in a nested fashion in the PLPM and provide positional information along the body axis. The lateral plate mesoderm then splits into the somatic and splanchnic layers. In the somatic layer of the PLPM, the expression of limb initiation genes appears in the limb-forming region, leading to limb bud initiation. Furthermore, past and current work in limbless amphioxus and lampreys suggests that evolutionary changes in developmental programs occurred during the acquisition of paired fins during vertebrate evolution. This review presents these recent advances and discusses the mechanisms of limb field specification during development and evolution, with a focus on the role of Hox genes in this process.
      PubDate: 2016-05-19
      DOI: 10.3390/jdb4020018
      Issue No: Vol. 4, No. 2 (2016)
  • JDB, Vol. 4, Pages 19: Regulation of Silk Genes by Hox and Homeodomain
           Proteins in the Terminal Differentiated Silk Gland of the Silkworm Bombyx

    • Authors: Shigeharu Takiya, Takuya Tsubota, Mai Kimoto
      First page: 19
      Abstract: The silk gland of the silkworm Bombyx mori is a long tubular organ that is divided into several subparts along its anteroposterior (AP) axis. As a trait of terminal differentiation of the silk gland, several silk protein genes are expressed with unique regional specificities. Most of the Hox and some of the homeobox genes are also expressed in the differentiated silk gland with regional specificities. The expression patterns of Hox genes in the silk gland roughly correspond to those in embryogenesis showing “colinearity”. The central Hox class protein Antennapedia (Antp) directly regulates the expression of several middle silk gland–specific silk genes, whereas the Lin-1/Isl-1/Mec3 (LIM)-homeodomain transcriptional factor Arrowhead (Awh) regulates the expression of posterior silk gland–specific genes for silk fiber proteins. We summarize our results and discuss the usefulness of the silk gland of Bombyx mori for analyzing the function of Hox genes. Further analyses of the regulatory mechanisms underlying the region-specific expression of silk genes will provide novel insights into the molecular bases for target-gene selection and regulation by Hox and homeodomain proteins.
      PubDate: 2016-05-25
      DOI: 10.3390/jdb4020019
      Issue No: Vol. 4, No. 2 (2016)
  • JDB, Vol. 4, Pages 20: Hedgehog Signaling in Endochondral Ossification

    • Authors: Shinsuke Ohba
      First page: 20
      Abstract: Hedgehog (Hh) signaling plays crucial roles in the patterning and morphogenesis of various organs within the bodies of vertebrates and insects. Endochondral ossification is one of the notable developmental events in which Hh signaling acts as a master regulator. Among three Hh proteins in mammals, Indian hedgehog (Ihh) is known to work as a major Hh input that induces biological impact of Hh signaling on the endochondral ossification. Ihh is expressed in prehypertrophic and hypertrophic chondrocytes of developing endochondral bones. Genetic studies so far have demonstrated that the Ihh-mediated activation of Hh signaling synchronizes chondrogenesis and osteogenesis during endochondral ossification by regulating the following processes: (1) chondrocyte differentiation; (2) chondrocyte proliferation; and (3) specification of bone-forming osteoblasts. Ihh not only forms a negative feedback loop with parathyroid hormone-related protein (PTHrP) to maintain the growth plate length, but also directly promotes chondrocyte propagation. Ihh input is required for the specification of progenitors into osteoblast precursors. The combinatorial approaches of genome-wide analyses and mouse genetics will facilitate understanding of the regulatory mechanisms underlying the roles of Hh signaling in endochondral ossification, providing genome-level evidence of the potential of Hh signaling for the treatment of skeletal disorders.
      PubDate: 2016-06-03
      DOI: 10.3390/jdb4020020
      Issue No: Vol. 4, No. 2 (2016)
  • JDB, Vol. 4, Pages 21: Signalling by Transforming Growth Factor Beta
           Isoforms in Wound Healing and Tissue Regeneration

    • Authors: Richard Gilbert, Matthew Vickaryous, Alicia Viloria-Petit
      First page: 21
      Abstract: Transforming growth factor beta (TGFβ) signalling is essential for wound healing, including both non-specific scar formation and tissue-specific regeneration. Specific TGFβ isoforms and downstream mediators of canonical and non-canonical signalling play different roles in each of these processes. Here we review the role of TGFβ signalling during tissue repair, with a particular focus on the prototypic isoforms TGFβ1, TGFβ2, and TGFβ3. We begin by introducing TGFβ signalling and then discuss the role of these growth factors and their key downstream signalling mediators in determining the balance between scar formation and tissue regeneration. Next we discuss examples of the pleiotropic roles of TGFβ ligands during cutaneous wound healing and blastema-mediated regeneration, and how inhibition of the canonical signalling pathway (using small molecule inhibitors) blocks regeneration. Finally, we review various TGFβ-targeting therapeutic strategies that hold promise for enhancing tissue repair.
      PubDate: 2016-06-22
      DOI: 10.3390/jdb4020021
      Issue No: Vol. 4, No. 2 (2016)
  • JDB, Vol. 4, Pages 2: Hermes (Rbpms) is a Critical Component of RNP
           Complexes that Sequester Germline RNAs during Oogenesis

    • Authors: Tristan Aguero, Yi Zhou, Malgorzata Kloc, Patrick Chang, Evelyn Houliston, Mary King
      First page: 2
      Abstract: The germ cell lineage in Xenopus is specified by the inheritance of germ plasm that assembles within the mitochondrial cloud or Balbiani body in stage I oocytes. Specific RNAs, such as nanos1, localize to the germ plasm. nanos1 has the essential germline function of blocking somatic gene expression and thus preventing Primordial Germ Cell (PGC) loss and sterility. Hermes/Rbpms protein and nanos RNA co-localize within germinal granules, diagnostic electron dense particles found within the germ plasm. Previous work indicates that nanos accumulates within the germ plasm through a diffusion/entrapment mechanism. Here we show that Hermes/Rbpms interacts with nanos through sequence specific RNA localization signals found in the nanos-3′UTR. Importantly, Hermes/Rbpms specifically binds nanos, but not Vg1 RNA in the nucleus of stage I oocytes. In vitro binding data show that Hermes/Rbpms requires additional factors that are present in stage I oocytes in order to bind nanos1. One such factor may be hnRNP I, identified in a yeast-2-hybrid screen as directly interacting with Hermes/Rbpms. We suggest that Hermes/Rbpms functions as part of a RNP complex in the nucleus that facilitates selection of germline RNAs for germ plasm localization. We propose that Hermes/Rbpms is required for nanos RNA to form within the germinal granules and in this way, participates in the germline specific translational repression and sequestration of nanos RNA.
      PubDate: 2016-01-19
      DOI: 10.3390/jdb4010002
      Issue No: Vol. 4, No. 1 (2016)
  • JDB, Vol. 4, Pages 3: Notochord Cells in Intervertebral Disc Development
           and Degeneration

    • Authors: Matthew McCann, Cheryle Séguin
      First page: 3
      Abstract: The intervertebral disc is a complex structure responsible for flexibility, multi-axial motion, and load transmission throughout the spine. Importantly, degeneration of the intervertebral disc is thought to be an initiating factor for back pain. Due to a lack of understanding of the pathways that govern disc degeneration, there are currently no disease-modifying treatments to delay or prevent degenerative disc disease. This review presents an overview of our current understanding of the developmental processes that regulate intervertebral disc formation, with particular emphasis on the role of the notochord and notochord-derived cells in disc homeostasis and how their loss can result in degeneration. We then describe the role of small animal models in understanding the development of the disc and their use to interrogate disc degeneration and associated pathologies. Finally, we highlight essential development pathways that are associated with disc degeneration and/or implicated in the reparative response of the tissue that might serve as targets for future therapeutic approaches.
      PubDate: 2016-01-21
      DOI: 10.3390/jdb4010003
      Issue No: Vol. 4, No. 1 (2016)
  • JDB, Vol. 4, Pages 4: Cell Fate Decisions During Breast Cancer Development

    • Authors: Kayla Gross, Ania Wronski, Adam Skibinski, Sarah Phillips, Charlotte Kuperwasser
      First page: 4
      Abstract: During the formation of breast cancer, many genes become altered as cells evolve progressively from normal to a pre-malignant to a malignant state of growth. How mutations in genes lead to specific subtypes of human breast cancer is only partially understood. Here we review how initial genetic or epigenetic alterations within mammary epithelial cells (MECs) can alter cell fate decisions and put pre-malignant cells on a path towards cancer development with specific phenotypes. Understanding the early stages of breast cancer initiation and progression and how normal developmental processes are hijacked during transformation has significant implications for improving early detection and prevention of breast cancer. In addition, insights gleaned from this understanding may also be important for developing subtype-specific treatment options.
      PubDate: 2016-01-22
      DOI: 10.3390/jdb4010004
      Issue No: Vol. 4, No. 1 (2016)
  • JDB, Vol. 4, Pages 5: Acknowledgement to Reviewers of Journal of
           Developmental Biology in 2015

    • Authors: Journal of Developmental Biology Editorial Office
      First page: 5
      Abstract: The editors of Journal of Developmental Biology would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015. [...]
      PubDate: 2016-01-25
      DOI: 10.3390/jdb4010005
      Issue No: Vol. 4, No. 1 (2016)
  • JDB, Vol. 4, Pages 6: Alterations in Synthesis and Repair of DNA during
           the Development of Loach Misgurnus fossilis

    • Authors: Leonid Gening, Andrei Lakhin, Irina Makarova, Valentina Nenasheva, Ludmila Andreeva, Vyacheslav Tarantul
      First page: 6
      Abstract: Using a modified radiolabeled primer extension method (we named this modification misGvA—“misincorporation of G versus A”) we have investigated the DNA synthesis and repair at early and late stages of development of loach Misgurnus fossilis. The misincorporation activity of DNA polymerase iota (Pol ι) in wild-type loach could not be detected by this method at any stage of loach development. In transgenic loach overexpressing human Pol ι we have shown that the bypassing of DNA synthesis arrest after incorporation of mismatched nucleotide by Pol ι (the T-stop) was not associated with this enzyme. Non-transgenic loach larvae are virtually lacking the capacity for error correction of DNA duplex containing a mismatched nucleotide. Such repair activity develops only in the adult fish. It appears that the initial stages of development are characterized by more intensive DNA synthesis, while in terminal stages the repair activities become more prominent. The misGvA approach clearly indicates substantial changes in the DNA synthesis intensity, although the role of particular replicative and repair DNA polymerases in this process requires further study.
      PubDate: 2016-01-27
      DOI: 10.3390/jdb4010006
      Issue No: Vol. 4, No. 1 (2016)
  • JDB, Vol. 4, Pages 7: Restricted Pax3 Deletion within the Neural Tube
           Results in Congenital Hydrocephalus

    • Authors: Hong-Ming Zhou, Simon Conway
      First page: 7
      Abstract: Congenital hydrocephalus is a common birth-defect whose developmental origins are poorly understood. Pax3-null mutants show defects in myogenesis, neural tube closure, neural crest morphogenesis, and heart development that, consequently, results in embryonic lethality. Here we demonstrate that conditional deletion of the mouse Pax3 transcription factor results in fully-penetrant congenital obstructive hydrocephalus. To identify the role of Pax3 during cranial development, we deleted Pax3 within the neuroepithelium (via Pax7−Cre), in the neural crest (via P0-Cre), and in both the neuroepithelium and the neural crest (via Wnt1-Cre). Only conditional mutants generated using Pax7−Cre or Wnt1-Cre developed early onset congenital hydrocephalus due to stenosis of the third ventricle, suggesting that loss of neuroepithelial Pax3 is sufficient to disturb third ventricle morphogenesis. Dilation of lateral ventricles occurs as early as E14.5, and lineage-mapping revealed that the neuroepithelial cells in the conditional mutants are present, but fail to undergo normal differentiation at the stenotic site. Concomitant with a narrowing of the mutant third ventricle, we detected ectopic apoptosis, reduced proliferation, and abnormal β-catenin localization. Furthermore, consistent with the overlapping expression pattern of Pax3 and Pax7 in early cranial neuroepithelium, we demonstrated a combinatorial role, as compound Pax3/Pax7 heterozygotes display partially-penetrant congenital hydrocephalus. These murine data provide an experimental paradigm underpinning clinical observations of the presence of PAX3 mutations in some hydrocephalic patients.
      PubDate: 2016-02-01
      DOI: 10.3390/jdb4010007
      Issue No: Vol. 4, No. 1 (2016)
  • JDB, Vol. 4, Pages 8: Solving Classification Problems for Large Sets of
           Protein Sequences with the Example of Hox and ParaHox Proteins

    • Authors: Stefanie Hueber, Tancred Frickey
      First page: 8
      Abstract: Phylogenetic methods are key to providing models for how a given protein family evolved. However, these methods run into difficulties when sequence divergence is either too low or too high. Here, we provide a case study of Hox and ParaHox proteins so that additional insights can be gained using a new computational approach to help solve old classification problems. For two (Gsx and Cdx) out of three ParaHox proteins the assignments differ between the currently most established view and four alternative scenarios. We use a non-phylogenetic, pairwise-sequence-similarity-based method to assess which of the previous predictions, if any, are best supported by the sequence-similarity relationships between Hox and ParaHox proteins. The overall sequence-similarities show Gsx to be most similar to Hox2–3, and Cdx to be most similar to Hox4–8. The results indicate that a purely pairwise-sequence-similarity-based approach can provide additional information not only when phylogenetic inference methods have insufficient information to provide reliable classifications (as was shown previously for central Hox proteins), but also when the sequence variation is so high that the resulting phylogenetic reconstructions are likely plagued by long-branch-attraction artifacts.
      PubDate: 2016-02-04
      DOI: 10.3390/jdb4010008
      Issue No: Vol. 4, No. 1 (2016)
  • JDB, Vol. 4, Pages 9: The Roles of Aquaporins in Plant Stress Responses

    • Authors: Zunaira Afzal, T. Howton, Yali Sun, M. Mukhtar
      First page: 9
      Abstract: Aquaporins are membrane channel proteins ubiquitously present in all kingdoms of life. Although aquaporins were originally discovered as water channels, their roles in the transport of small neutral solutes, gasses, and metal ions are now well established. Plants contain the largest number and greatest diversity of aquaporin homologs with diverse subcellular localization patterns, gating properties, and solute specificity. The roles of aquaporins in physiological functions throughout plant growth and development are well known. As an integral regulator of plant–water relations, they are presumed to play an important role in plant defense responses against biotic and abiotic stressors. This review highlights involvement of various aquaporin homologs in plant stress responses against a variety of environmental stresses that disturb plant cell osmotic balance and nutrient homeostasis.
      PubDate: 2016-02-04
      DOI: 10.3390/jdb4010009
      Issue No: Vol. 4, No. 1 (2016)
  • JDB, Vol. 4, Pages 10: HoxA Genes and the Fin-to-Limb Transition in

    • Authors: João Leite-Castro, Vanessa Beviano, Pedro Rodrigues, Renata Freitas
      First page: 10
      Abstract: HoxA genes encode for important DNA-binding transcription factors that act during limb development, regulating primarily gene expression and, consequently, morphogenesis and skeletal differentiation. Within these genes, HoxA11 and HoxA13 were proposed to have played an essential role in the enigmatic evolutionary transition from fish fins to tetrapod limbs. Indeed, comparative gene expression analyses led to the suggestion that changes in their regulation might have been essential for the diversification of vertebrates’ appendages. In this review, we highlight three potential modifications in the regulation and function of these genes that may have boosted appendage evolution: (1) the expansion of polyalanine repeats in the HoxA11 and HoxA13 proteins; (2) the origin of +a novel long-non-coding RNA with a possible inhibitory function on HoxA11; and (3) the acquisition of cis-regulatory elements modulating 5’ HoxA transcription. We discuss the relevance of these mechanisms for appendage diversification reviewing the current state of the art and performing additional comparative analyses to characterize, in a phylogenetic framework, HoxA11 and HoxA13 expression, alanine composition within the encoded proteins, long-non-coding RNAs and cis-regulatory elements.
      PubDate: 2016-02-17
      DOI: 10.3390/jdb4010010
      Issue No: Vol. 4, No. 1 (2016)
  • JDB, Vol. 4, Pages 11: Histologic Assessment of Drug-Eluting Grafts
           Related to Implantation Site

    • Authors: Jean-Christophe Tille, Sarra de Valence, Delia Mandracchia, Benjamin Nottelet, Francesco Innocente, Robert Gurny, Michael Möller, Beat Walpoth
      First page: 11
      Abstract: Drug-eluting vascular prostheses represent a new direction in vascular surgery to reduce early thrombosis and late intimal hyperplasia for small calibre grafts. Subcutaneous implantation in rats is a rapid and cost-effective screening model to assess the drug-elution effect and could, to some extent, be useful to forecast results for vascular prostheses. We compared biological and histological responses to scaffolds in different implantation sites. Polycaprolactone (PCL), paclitaxel-loaded PCL (PCL-PTX) and dexamethasone-loaded PCL (PCL-DXM) electrospun scaffolds were implanted subcutaneously and in an infrarenal abdominal aortic model in rats for up to 12 weeks. At the conclusion of the study, a histological analysis was performed. Cellular graft invasion revealed differences in the progression of cellular infiltration between PCL-PTX and PCL/PCL-DXM groups in both models. Cell infiltration increased over time in the aortic model compared to the subcutaneous model for all groups. Cell counting revealed major differences in fibroblast, macrophage and giant cell graft colonisation in all groups and models over time. Macrophages and giant cells increased in the PCL aortic model; whereas in the subcutaneous model these cell types increased only after three weeks or even decreased in the drug-eluting PCL groups. Other major findings were observed only in the aortic replacement such as extracellular matrix deposition and neo-angiogenesis. The subcutaneous implant model can be used for screening, especially when drug-eluting effects are studied. However, major histological differences were observed in cell type reaction and depth of cell penetration compared to the aortic model. Our results demonstrate that the implantation site is a critical determinant of the biological response.
      PubDate: 2016-02-20
      DOI: 10.3390/jdb4010011
      Issue No: Vol. 4, No. 1 (2016)
  • JDB, Vol. 4, Pages 12: An Overview of Hox Genes in Lophotrochozoa:
           Evolution and Functionality

    • Authors: Marco Barucca, Adriana Canapa, Maria Biscotti
      First page: 12
      Abstract: Hox genes are regulators of animal embryonic development. Changes in the number and sequence of Hox genes as well as in their expression patterns have been related to the evolution of the body plan. Lophotrochozoa is a clade of Protostomia characterized by several phyla which show a wide morphological diversity. Despite that the works summarized in this review emphasize the fragmentary nature of the data available regarding the presence and expression of Hox genes, they also offer interesting insight into the evolution of the Hox cluster and the role played by Hox genes in several phyla. However, the number of genes involved in the cluster of the lophotrochozoan ancestor is still a question of debate. The data presented here suggest that at least nine genes were present while two other genes, Lox4 and Post-2, may either have been present in the ancestor or may have arisen as a result of duplication in the Brachiopoda-Mollusca-Annelida lineage. Spatial and temporal collinearity is a feature of Hox gene expression which was probably present in the ancestor of deuterostomes and protostomes. However, in Lophotrochozoa, it has been detected in only a few species belonging to Annelida and Mollusca.
      PubDate: 2016-03-19
      DOI: 10.3390/jdb4010012
      Issue No: Vol. 4, No. 1 (2016)
  • JDB, Vol. 1, Pages 1-2: Developmental Biology — Expanding the

    • Authors: Andy Wessels
      Pages: 1 - 2
      Abstract: Developmental biology is arguably the most exciting field of study within the biological sciences. To elucidate how complex organisms develop from a single cell into a complex organism is a quest that has captured the minds of many great scientists. [...]
      PubDate: 2012-09-25
      DOI: 10.3390/jdb1010001
      Issue No: Vol. 1, No. 1 (2012)
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