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ELife Sep 2023Development of the dorsal aorta is a key step in the establishment of the adult blood-forming system, since hematopoietic stem and progenitor cells (HSPCs) arise from...
Development of the dorsal aorta is a key step in the establishment of the adult blood-forming system, since hematopoietic stem and progenitor cells (HSPCs) arise from ventral aortic endothelium in all vertebrate animals studied. Work in zebrafish has demonstrated that arterial and venous endothelial precursors arise from distinct subsets of lateral plate mesoderm. Here, we profile the transcriptome of the earliest detectable endothelial cells (ECs) during zebrafish embryogenesis to demonstrate that tissue-specific EC programs initiate much earlier than previously appreciated, by the end of gastrulation. Classic studies in the chick embryo showed that paraxial mesoderm generates a subset of somite-derived endothelial cells (SDECs) that incorporate into the dorsal aorta to replace HSPCs as they exit the aorta and enter circulation. We describe a conserved program in the zebrafish, where a rare population of endothelial precursors delaminates from the dermomyotome to incorporate exclusively into the developing dorsal aorta. Although SDECs lack hematopoietic potential, they act as a local niche to support the emergence of HSPCs from neighboring hemogenic endothelium. Thus, at least three subsets of ECs contribute to the developing dorsal aorta: vascular ECs, hemogenic ECs, and SDECs. Taken together, our findings indicate that the distinct spatial origins of endothelial precursors dictate different cellular potentials within the developing dorsal aorta.
Topics: Chick Embryo; Animals; Zebrafish; Arteries; Hematopoietic Stem Cells; Hemangioblasts; Aorta
PubMed: 37695317
DOI: 10.7554/eLife.58300 -
Current Topics in Developmental Biology 2024Embryonic skeletal muscle growth is contingent upon a population of somite derived satellite cells, however, the contribution of these cells to early postnatal skeletal... (Review)
Review
Embryonic skeletal muscle growth is contingent upon a population of somite derived satellite cells, however, the contribution of these cells to early postnatal skeletal muscle growth remains relatively high. As prepubertal postnatal development proceeds, the activity and contribution of satellite cells to skeletal muscle growth diminishes. Eventually, at around puberty, a population of satellite cells escapes terminal commitment, continues to express the paired box transcription factor Pax7, and reside in a quiescent state orbiting the myofiber periphery adjacent to the basal lamina. After adolescence, some satellite cell contributions to muscle maintenance and adaptation occur, however, their necessity is reduced relative to embryonic, early postnatal, and prepubertal growth.
Topics: Satellite Cells, Skeletal Muscle; Animals; Muscle, Skeletal; Humans; Muscle Development; PAX7 Transcription Factor; Cell Differentiation
PubMed: 38670701
DOI: 10.1016/bs.ctdb.2024.01.020 -
Journal of Comparative Physiology. B,... Aug 2023The kinetics of myosin controls the speed and power of muscle contraction. Mammalian skeletal muscles express twelve kinetically different myosin heavy chain (MyHC)... (Review)
Review
The kinetics of myosin controls the speed and power of muscle contraction. Mammalian skeletal muscles express twelve kinetically different myosin heavy chain (MyHC) genes which provides a wide range of muscle speeds to meet different functional demands. Myogenic progenitors from diverse craniofacial and somitic mesoderm specify muscle allotypes with different repertoires for MyHC expression. This review provides a brief synopsis on the historical and current views on how cell lineage, neural impulse patterns, and thyroid hormone influence MyHC gene expression in muscles of the limb allotype during development and in adult life and the molecular mechanisms thereof. During somitic myogenesis, embryonic and foetal myoblast lineages form slow and fast primary and secondary myotube ontotypes which respond differently to postnatal neural and thyroidal influences to generate fully differentiated fibre phenotypes. Fibres of a given phenotype may arise from myotubes of different ontotypes which retain their capacity to respond differently to neural and thyroidal influences during postnatal life. This gives muscles physiological plasticity to adapt to fluctuations in thyroid hormone levels and patterns of use. The kinetics of MyHC isoforms vary inversely with animal body mass. Fast 2b fibres are specifically absent in muscles involved in elastic energy saving in hopping marsupials and generally absent in large eutherian mammals. Changes in MyHC expression are viewed in the context of the physiology of the whole animal. The roles of myoblast lineage and thyroid hormone in regulating MyHC gene expression are phylogenetically the most ancient while that of neural impulse patterns the most recent.
Topics: Animals; Myosin Heavy Chains; Phylogeny; Muscle, Skeletal; Muscle Fibers, Skeletal; Myosins; Marsupialia
PubMed: 37277594
DOI: 10.1007/s00360-023-01499-0 -
BioRxiv : the Preprint Server For... Apr 2024Mutations in the gene lead to Duchenne muscular dystrophy, a severe X-linked neuromuscular disorder that manifests itself as young boys acquire motor functions. DMD is...
Mutations in the gene lead to Duchenne muscular dystrophy, a severe X-linked neuromuscular disorder that manifests itself as young boys acquire motor functions. DMD is typically diagnosed at 2 to 4 years of age, but the absence of dystrophin negatively impacts muscle structure and function before overt symptoms appear in patients, which poses a serious challenge in the optimization of standards of care. In this report, we investigated the early consequences of dystrophin deficiency during skeletal muscle development. We used single-cell transcriptome profiling to characterize the myogenic trajectory of human pluripotent stem cells and showed that DMD cells bifurcate to an alternative branch when they reach the somite stage. Here, dystrophin deficiency was linked to marked dysregulations of cell junction protein families involved in the cell state transitions characteristic of embryonic somitogenesis. Altogether, this work demonstrates that , dystrophin deficiency has deleterious effects on cell-cell communication during myogenic development, which should be considered in future therapeutic strategies for DMD.
PubMed: 38106055
DOI: 10.1101/2023.12.05.569919 -
Frontiers in Physiology 2024Initially, the two members of class 18 myosins, Myo18A and Myo18B, appeared to exhibit highly divergent functions, complicating the assignment of class-specific... (Review)
Review
Initially, the two members of class 18 myosins, Myo18A and Myo18B, appeared to exhibit highly divergent functions, complicating the assignment of class-specific functions. However, the identification of a striated muscle-specific isoform of Myo18A, Myo18Aγ, suggests that class 18 myosins may have evolved to complement the functions of conventional class 2 myosins in sarcomeres. Indeed, both genes, and , are predominantly expressed in the heart and somites, precursors of skeletal muscle, of developing mouse embryos. Genetic deletion of either gene in mice is embryonic lethal and is associated with the disorganization of cardiac sarcomeres. Moreover, Myo18Aγ and Myo18B localize to sarcomeric A-bands, albeit the motor (head) domains of these unconventional myosins have been both deduced and biochemically demonstrated to exhibit negligible ATPase activity, a hallmark of motor proteins. Instead, Myo18Aγ and Myo18B presumably coassemble with thick filaments and provide structural integrity and/or internal resistance through interactions with F-actin and/or other proteins. In addition, Myo18Aγ and Myo18B may play distinct roles in the assembly of myofibrils, which may arise from actin stress fibers containing the α-isoform of Myo18A, Myo18Aα. The β-isoform of Myo18A, Myo18Aβ, is similar to Myo18Aα, except that it lacks the N-terminal extension, and may serve as a negative regulator through heterodimerization with either Myo18Aα or Myo18Aγ. In this review, we contend that Myo18Aγ and Myo18B are essential for myofibril structure and function in striated muscle cells, while α- and β-isoforms of Myo18A play diverse roles in nonmuscle cells.
PubMed: 38784114
DOI: 10.3389/fphys.2024.1401717 -
The American Journal of Pathology Sep 2023The SF3B4 gene encodes a highly conserved protein that plays a critical role in mRNA splicing. Mutations in this gene are known to cause Nager syndrome, a rare...
The SF3B4 gene encodes a highly conserved protein that plays a critical role in mRNA splicing. Mutations in this gene are known to cause Nager syndrome, a rare craniofacial disorder. Although SF3B4 expression is detected in the optic vesicle before it is detected in the limb and somite, the role of SF3B4 in the eye is not well understood. This study investigated the function of sf3b4 in the retina by performing transcriptome profiles, immunostaining, and behavioral analysis of sf3b4 mutant zebrafish. Results from this study suggest that dysregulation of the spliceosome complex affects not only craniofacial development but also retinogenesis. Zebrafish lacking functional sf3b4 displayed characteristics similar to retinitis pigmentosa (RP), marked by severe retinal pigment epithelium defects and rod degeneration. Pathway analysis revealed altered retinol metabolism and retinoic acid signaling in the sf3b4 mutants. Supplementation of retinoic acid rescued key cellular phenotypes observed in the sf3b4 mutants, offering potential therapeutic strategies for RP in the future. In conclusion, this study sheds light on the previously unknown role of SF3B4 in retinogenesis and provides insights into the underlying mechanisms of RP.
Topics: Animals; Spliceosomes; Zebrafish; RNA Splicing Factors; Mutation; Retinitis Pigmentosa; Tretinoin
PubMed: 37263342
DOI: 10.1016/j.ajpath.2023.05.008 -
BioRxiv : the Preprint Server For... Feb 2024Embryonic organoids are emerging as powerful models for studying early mammalian development. For example, stem cell-derived 'gastruloids' form elongating structures...
Embryonic organoids are emerging as powerful models for studying early mammalian development. For example, stem cell-derived 'gastruloids' form elongating structures containing all three germ layers. However, although elongated, human gastruloids do not morphologically resemble post-implantation embryos. Here we show that a specific, discontinuous regimen of retinoic acid (RA) robustly induces human gastruloids with embryo-like morphological structures, including a neural tube and segmented somites. Single cell RNA-seq (sc-RNA-seq) further reveals that these human 'RA-gastruloids' contain more advanced cell types than conventional gastruloids, including neural crest cells, renal progenitor cells, skeletal muscle cells, and, rarely, neural progenitor cells. We apply a new approach to computationally stage human RA-gastruloids relative to somite-resolved mouse embryos, early human embryos and other gastruloid models, and find that the developmental stage of human RA-gastruloids is comparable to that of E9.5 mouse embryos, although some cell types show greater or lesser progression. We chemically perturb WNT and BMP signaling in human RA-gastruloids and find that these signaling pathways regulate somite patterning and neural tube length, respectively, while genetic perturbation of the transcription factors PAX3 and TBX6 markedly compromises the formation of neural crest and somites/renal cells, respectively. Human RA-gastruloids complement other embryonic organoids in serving as a simple, robust and screenable model for decoding early human embryogenesis.
PubMed: 38405970
DOI: 10.1101/2024.02.10.579769 -
Child's Nervous System : ChNS :... Dec 2023Chiari III malformation is considered to be a rare congenital abnormality in human with very high mortality rates. Seventy percent of Chiari III is found to be...
Chiari III malformation is considered to be a rare congenital abnormality in human with very high mortality rates. Seventy percent of Chiari III is found to be associated with C1 arch defect as reported by Cakirer (Clin Imaging 27:1-4, 2003). The herniation of posterior fossa elements or dysplastic neural tissue is a must to stamp it as Chiari 3 malformation. The malformation is a result of the abnormal development of craniovertebral junction (CVJ). The CVJ developed from the occipital somites and the first spinal sclerotome. The major role in the development of the CVJ is played by the fourth occipital somite, which is otherwise known as "proatlas." The Chiari III anomalies are due to a result of proatlas defect, which results from failures of segmentation, failures of fusion of different components of each bone, or hypoplasia and ankylosis. We are presenting a case of a 1-year 4-month-old female child who presented with pedunculated swelling at the suboccipital region. The swelling was cystic and with pulsation. On evaluation, we found Chiari III anomaly with C1 posterior arch deficiency (proatlas defect). He was surgically managed. The outcome of the patient was good. Despite literature concluding Chiari 3 malformation with an unfavorable outcome, however, meticulous management and good pre- and postoperative care, physical therapy, and follow-up are necessary for good outcome.
Topics: Female; Humans; Infant; Arnold-Chiari Malformation; Cranial Fossa, Posterior; Decompression, Surgical; Head; Magnetic Resonance Imaging; Spine
PubMed: 37368065
DOI: 10.1007/s00381-023-06044-6 -
Nature Communications Oct 2023Mutations of several genes cause incomplete penetrance and variable expressivity of phenotypes, which are usually attributed to modifier genes or gene-environment...
Mutations of several genes cause incomplete penetrance and variable expressivity of phenotypes, which are usually attributed to modifier genes or gene-environment interactions. Here, we show stochastic gene expression underlies the variability of somite segmentation defects in embryos mutant for segmentation clock genes her1 or her7. Phenotypic strength is further augmented by low temperature and hypoxia. By performing live imaging of the segmentation clock reporters, we further show that groups of cells with higher oscillation amplitudes successfully form somites while those with lower amplitudes fail to do so. In unfavorable environments, the number of cycles with high amplitude oscillations and the number of successful segmentations proportionally decrease. These results suggest that individual oscillation cycles stochastically fail to pass a threshold amplitude, resulting in segmentation defects in mutants. Our quantitative methodology is adaptable to investigate variable phenotypes of mutant genes in different tissues.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Zebrafish; Zebrafish Proteins; Somites; Phenotype; Gene Expression; Gene Expression Regulation, Developmental; Body Patterning
PubMed: 37838784
DOI: 10.1038/s41467-023-42220-7 -
Fish Physiology and Biochemistry Dec 2023Neural tube defects are severe congenital disorders of the central nervous system that originate during embryonic development when the neural tube fails to close...
Neural tube defects are severe congenital disorders of the central nervous system that originate during embryonic development when the neural tube fails to close completely. It affects one to two infants per 1000 births. The aetiology is multifactorial with contributions from both genetic and environmental factors. Dysregulated epigenetic mechanisms, in particular the abnormal genome-wide methylation during embryogenesis, have been linked to developmental abnormalities including neural tube defects. The current study investigated the influence of decitabine (DCT), a DNA methylation inhibitor, on embryonic development in zebrafish, with a focus on neural tube formation. The developing zebrafish embryos were exposed to graded concentrations of decitabine (from 13.69 μM to 1 mM) before the onset of neurulation. The developmental process was monitored at regular time intervals post fertilization. At 120 h post fertilization, the developing embryos were inspected individually to determine the incidence and severity of neural tube defects. Using alizarin red staining, the cranial and caudal neural tube morphology was examined in formaldehyde fixed larvae. Anomalies in neural tube and somite development, as well as a delay in hatching, were discovered at an early stage of development. As development continued, neural tube defects became increasingly evident, and there was a concentration-dependent rise in the prevalence and severity of various neural tube defects. 90% of growing embryos in the group exposed to decitabine 1 mM had multiple neural tube malformations, and 10% had isolated neural tube defects. With several abnormalities, the caudal region of the neural tube was seriously compromised. The histopathological studies supported the malformations in neural tube. Our study revealed the harmful impact of decitabine on the development of the neural tube in growing zebrafish. Moreover, these findings support the hypothesis that the hypomethylation during embryonic development causes neural tube defects.
Topics: Humans; Pregnancy; Female; Animals; Zebrafish; Decitabine; Neural Tube Defects; Central Nervous System; DNA Methylation; Neural Tube
PubMed: 37982970
DOI: 10.1007/s10695-023-01261-x