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Physiology (Bethesda, Md.) Mar 2023The significance of the coupling delay, which is the time required for interactions between coupled oscillators, in various oscillatory dynamics has been investigated... (Review)
Review
The significance of the coupling delay, which is the time required for interactions between coupled oscillators, in various oscillatory dynamics has been investigated mathematically for more than three decades, but its biological significance has been revealed only recently. In the segmentation clock, which regulates the periodic formation of somites in embryos, Hes7 expression oscillates synchronously between neighboring presomitic mesoderm (PSM) cells, and this synchronized oscillation is controlled by Notch signaling-mediated coupling between PSM cells. Recent studies have shown that inappropriate coupling delays dampen and desynchronize Hes7 oscillations, as simulated mathematically, leading to the severe fusion of somites and somite-derived tissues such as the vertebrae and ribs. These results indicate the biological significance of the coupling delay in synchronized Hes7 oscillations in the segmentation clock. The recent development of an in vitro PSM-like system will facilitate the detailed analysis of the coupling delay in synchronized oscillations.
Topics: Humans; Basic Helix-Loop-Helix Transcription Factors; Somites; Signal Transduction
PubMed: 36256636
DOI: 10.1152/physiol.00023.2022 -
Developmental Biology May 2020Vertebrate head morphogenesis involves carefully-orchestrated tissue growth and cell movements of the mesoderm and neural crest to form the distinct craniofacial...
Vertebrate head morphogenesis involves carefully-orchestrated tissue growth and cell movements of the mesoderm and neural crest to form the distinct craniofacial pattern. To better understand structural birth defects, it is important that we characterize the dynamics of these processes and learn how they rely on each other. Here we examine this question during chick head morphogenesis using time-lapse imaging, computational modeling, and experiments. We find that head mesodermal cells in culture move in random directions as individuals and move faster in the presence of neural crest cells. In vivo, mesodermal cells migrate in a directed manner and maintain neighbor relationships; neural crest cells travel through the mesoderm at a faster speed. The mesoderm grows with a non-uniform spatio-temporal profile determined by BrdU labeling during the period of faster and more-directed neural crest collective migration through this domain. We use computer simulations to probe the robustness of neural crest stream formation by varying the spatio-temporal growth profile of the mesoderm. We follow this with experimental manipulations that either stop mesoderm growth or prevent neural crest migration and observe changes in the non-manipulated cell population, implying a dynamic feedback between tissue growth and neural crest cell signaling to confer robustness to the system. Overall, we present a novel descriptive analysis of mesoderm and neural crest cell dynamics that reveals the coordination and co-dependence of these two cell populations during head morphogenesis.
Topics: Animals; Cell Division; Cell Movement; Cells, Cultured; Chick Embryo; Chickens; Computer Simulation; Coturnix; Ectoderm; Head; Mesoderm; Models, Biological; Morphogenesis; Neural Crest; Neural Tube; Time-Lapse Imaging
PubMed: 32084354
DOI: 10.1016/j.ydbio.2020.02.010 -
Disease Models & Mechanisms May 2023Syndromic birth defects are rare diseases that can present with seemingly pleiotropic comorbidities. Prime examples are rare congenital heart and cardiovascular...
Syndromic birth defects are rare diseases that can present with seemingly pleiotropic comorbidities. Prime examples are rare congenital heart and cardiovascular anomalies that can be accompanied by forelimb defects, kidney disorders and more. Whether such multi-organ defects share a developmental link remains a key question with relevance to the diagnosis, therapeutic intervention and long-term care of affected patients. The heart, endothelial and blood lineages develop together from the lateral plate mesoderm (LPM), which also harbors the progenitor cells for limb connective tissue, kidneys, mesothelia and smooth muscle. This developmental plasticity of the LPM, which founds on multi-lineage progenitor cells and shared transcription factor expression across different descendant lineages, has the potential to explain the seemingly disparate syndromic defects in rare congenital diseases. Combining patient genome-sequencing data with model organism studies has already provided a wealth of insights into complex LPM-associated birth defects, such as heart-hand syndromes. Here, we summarize developmental and known disease-causing mechanisms in early LPM patterning, address how defects in these processes drive multi-organ comorbidities, and outline how several cardiovascular and hematopoietic birth defects with complex comorbidities may be LPM-associated diseases. We also discuss strategies to integrate patient sequencing, data-aggregating resources and model organism studies to mechanistically decode congenital defects, including potentially LPM-associated orphan diseases. Eventually, linking complex congenital phenotypes to a common LPM origin provides a framework to discover developmental mechanisms and to anticipate comorbidities in congenital diseases affecting the cardiovascular system and beyond.
Topics: Animals; Cardiovascular Diseases; Body Patterning; Heart; Heart Defects, Congenital; Transcription Factors; Mesoderm; Gene Expression Regulation, Developmental
PubMed: 37125615
DOI: 10.1242/dmm.049735 -
FEBS Letters Dec 2019Sexual dimorphisms contribute, at least in part, to the severity and occurrence of a broad range of neurodegenerative, cardiovascular, and bone disorders. In addition to... (Review)
Review
Sexual dimorphisms contribute, at least in part, to the severity and occurrence of a broad range of neurodegenerative, cardiovascular, and bone disorders. In addition to hormonal factors, increasing evidence suggests that stem cell-intrinsic mechanisms account for sex-specific differences in human physiology and pathology. Here, we discuss sex-related intrinsic mechanisms in adult stem cell populations, namely mesoderm-derived stem cells, neural stem cells (NSCs), and neural crest-derived stem cells (NCSCs), and their implications for stem cell differentiation and regeneration. We particularly focus on sex-specific differences in stem cell-mediated bone regeneration, in neuronal development, and in NSC-mediated neuroprotection. Moreover, we review our own recently published observations regarding the sex-dependent role of NF-κB-p65 in neuroprotection of human NCSC-derived neurons and sex differences in NCSC-related disorders, so-called neurocristopathies. These observations are in accordance with the increasing evidence pointing toward sex-specific differences in neurocristopathies and degenerative diseases like Parkinson's disease or osteoporosis. All findings discussed here indicate that sex-specific variability in stem cell biology may become a crucial parameter for the design of future treatment strategies.
Topics: Cell Differentiation; Female; Humans; Male; Mesoderm; NF-kappa B; Neural Crest; Neural Stem Cells; Neurons; Osteoporosis; Parkinson Disease; Sex Characteristics; eIF-2 Kinase
PubMed: 31529465
DOI: 10.1002/1873-3468.13606 -
Developmental Biology Jul 2020Initial limb chondrogenesis offers the first differentiated tissues that resemble the mature skeletal anatomy. It is a developmental progression of three tissues. The... (Review)
Review
Initial limb chondrogenesis offers the first differentiated tissues that resemble the mature skeletal anatomy. It is a developmental progression of three tissues. The limb begins with undifferentiated mesenchyme-1, some of which differentiates into condensations-2, and this tissue then transforms into cartilage-3. Each tissue is identified by physical characteristics of cell density, shape, and extracellular matrix composition. Tissue specific regimes of gene regulation underlie the diagnostic physical and chemical properties of these three tissues. These three tissue based regimes co-exist amid a background of other gene regulatory regimes within the same tissues and time-frame of limb development. The bio-molecular indicators of gene regulation reveal six identifiable patterns. Three of these patterns describe the unique bio-molecular indicators of each of the three tissues. A fourth pattern shares bio-molecular indicators between condensation and cartilage. Finally, a fifth pattern is composed of bio-molecular indicators that are found in undifferentiated mesenchyme prior to any condensation differentiation, then these bio-molecular indicators are upregulated in condensations and downregulated in undifferentiated mesenchyme. The undifferentiated mesenchyme that remains in between the condensations and cartilage, the interdigit, contains a unique set of bio-molecular indicators that exhibit dynamic behaviour during chondrogenesis and therefore argue for its own inclusion as a tissue in its own right and for more study into this process of differentiation.
Topics: Animals; Cartilage; Cell Differentiation; Chondrogenesis; Extracellular Matrix; Gene Expression Regulation, Developmental; Limb Buds; Mesoderm; Proteoglycans
PubMed: 32417169
DOI: 10.1016/j.ydbio.2020.04.009 -
Seminars in Cell & Developmental Biology Mar 2023Of all the cell types arising from the neural crest, ectomesenchyme is likely the most unusual. In contrast to the neuroglial cells generated by neural crest throughout... (Review)
Review
Of all the cell types arising from the neural crest, ectomesenchyme is likely the most unusual. In contrast to the neuroglial cells generated by neural crest throughout the embryo, consistent with its ectodermal origin, cranial neural crest-derived cells (CNCCs) generate many connective tissue and skeletal cell types in common with mesoderm. Whether this ectoderm-derived mesenchyme (ectomesenchyme) potential reflects a distinct developmental origin from other CNCC lineages, and/or epigenetic reprogramming of the ectoderm, remains debated. Whereas decades of lineage tracing studies have defined the potential of CNCC ectomesenchyme, these are being revisited by modern genetic techniques. Recent work is also shedding light on the extent to which intrinsic and extrinsic cues determine ectomesenchyme potential, and whether maintenance or reacquisition of CNCC multipotency influences craniofacial repair.
Topics: Neural Crest; Mesoderm; Ectoderm; Embryo, Mammalian
PubMed: 35331627
DOI: 10.1016/j.semcdb.2022.03.018 -
Genes Nov 2019During vertebrate embryogenesis, precise regulation of gene expression is crucial for proper cell fate determination. Much of what we know about vertebrate development... (Review)
Review
During vertebrate embryogenesis, precise regulation of gene expression is crucial for proper cell fate determination. Much of what we know about vertebrate development has been gleaned from experiments performed on embryos of the amphibian ; this review will focus primarily on studies of this model organism. An early critical step during vertebrate development is the formation of the three primary germ layers-ectoderm, mesoderm, and endoderm-which emerge during the process of gastrulation. While much attention has been focused on the induction of mesoderm and endoderm, it has become clear that differentiation of the ectoderm involves more than the simple absence of inductive cues; rather, it additionally requires the inhibition of mesendoderm-promoting genes. This review aims to summarize our current understanding of the various inhibitors of inappropriate gene expression in the presumptive ectoderm.
Topics: Animals; Cell Differentiation; Ectoderm; Endoderm; Gastrulation; Gene Expression Regulation, Developmental; Germ Layers; Mesoderm; Xenopus laevis
PubMed: 31698780
DOI: 10.3390/genes10110895 -
International Journal of Molecular... Jul 2023Scar formation during normal tissue regeneration in adults may result in noticeable cosmetic and functional defects and have a significant impact on the quality of life.... (Review)
Review
Scar formation during normal tissue regeneration in adults may result in noticeable cosmetic and functional defects and have a significant impact on the quality of life. In contrast, fetal tissues in the mid-gestation period are known to be capable of complete regeneration with the restitution of the initial architecture, organization, and functional activity. Successful treatments that are targeted to minimize scarring can be realized by understanding the cellular and molecular mechanisms of fetal wound regeneration. However, such experiments are limited by the inaccessibility of fetal material for comparable studies. For this reason, the molecular mechanisms of fetal regeneration remain unknown. Mesenchymal stromal cells (MSCs) are central to tissue repair because the molecules they secrete are involved in the regulation of inflammation, angiogenesis, and remodeling of the extracellular matrix. The mesodermal differentiation of human pluripotent stem cells (hPSCs) recapitulates the sequential steps of embryogenesis in vitro and provides the opportunity to generate the isogenic cell models of MSCs corresponding to different stages of human development. Further investigation of the functional activity of cells from stromal differon in a pro-inflammatory microenvironment will procure the molecular tools to better understand the fundamental mechanisms of fetal tissue regeneration. Herein, we review recent advances in the generation of clonal precursors of primitive mesoderm cells and MSCs from hPSCs and discuss critical factors that determine the functional activity of MSCs-like cells in a pro-inflammatory microenvironment in order to identify therapeutic targets for minimizing scarring.
Topics: Adult; Humans; Cicatrix; Quality of Life; Wound Healing; Mesoderm; Pluripotent Stem Cells
PubMed: 37569321
DOI: 10.3390/ijms241511945 -
Developmental Cell Jun 2023Mesenchymal-epithelial transition (MET) is a critical process in development, guiding tissue morphogenesis. In this issue of Developmental Cell, two studies, one by...
Mesenchymal-epithelial transition (MET) is a critical process in development, guiding tissue morphogenesis. In this issue of Developmental Cell, two studies, one by Gredler et al. and one by Abboud Asleh et al., reveal how multicellular rosettes critically contribute to MET in earliest notochord and lateral plate mesoderm formation, respectively.
Topics: Cell Differentiation; Mesoderm; Morphogenesis; Gastrula; Gastrulation
PubMed: 37279697
DOI: 10.1016/j.devcel.2023.04.018 -
Developmental Biology May 2022T is the founding member of the T-box family of transcription factors; family members are critical for cell fate decisions and tissue morphogenesis throughout the animal...
T is the founding member of the T-box family of transcription factors; family members are critical for cell fate decisions and tissue morphogenesis throughout the animal kingdom. T is expressed in the primitive streak and notochord with mouse mutant studies revealing its critical role in mesoderm formation in the primitive streak and notochord integrity. We previously demonstrated that misexpression of Tbx6 in the paraxial and lateral plate mesoderm results in embryos resembling Tbx15 and Tbx18 nulls. This, together with results from in vitro transcriptional assays, suggested that ectopically expressed Tbx6 can compete with endogenously expressed Tbx15 and Tbx18 at the binding sites of target genes. Since T-box proteins share a similar DNA binding domain, we hypothesized that misexpressing T in the paraxial and lateral plate mesoderm would also interfere with the endogenous Tbx15 and Tbx18, causing embryonic phenotypes resembling those seen upon Tbx6 expression in the somites and limbs. Interestingly, ectopic T expression led to distinct embryonic phenotypes, specifically, reduced-sized somites in embryos expressing the highest levels of T, which ultimately affects axis length and neural tube morphogenesis. We further demonstrate that ectopic T leads to ectopic expression of Tbx6 and Mesogenin 1, known targets of T. These results suggests that ectopic T expression contributes to the phenotype by activating its own targets rather than via a straight competition with endogenous T-box factors.
Topics: Animals; Ectopic Gene Expression; Embryonic Development; Gene Expression Regulation, Developmental; Mesoderm; Mice; Somites; T-Box Domain Proteins
PubMed: 35276131
DOI: 10.1016/j.ydbio.2022.02.010