Developmental Dynamics[JOURNAL]
Sun
200 papers
Hypoxia regulate developmental coronary angiogenesis potentially through VEGF-R2- and SOX17-mediated signaling.
Vitali HE, Kuschel B, Sherpa C … +9 more , Jones BW, Jacob N, Madiha SA, Elliott S, Dziennik E, Kreun L, Conatser C, Bhetwal BP, Sharma B
Dev Dyn · 2025 Feb · PMID 39360476 · Full text
BACKGROUND: The development of coronary vessels in embryonic mouse heart involves various progenitor populations, including sinus venosus (SV), endocardium, and proepicardium. ELA/APJ signaling is known to regulate coron...
BACKGROUND: The development of coronary vessels in embryonic mouse heart involves various progenitor populations, including sinus venosus (SV), endocardium, and proepicardium. ELA/APJ signaling is known to regulate coronary growth from the SV, whereas VEGF-A/VEGF-R2 signaling controls growth from the endocardium. Previous studies suggest hypoxia might regulate coronary growth, but its specific downstream pathways are unclear. In this study, we further investigated the role of hypoxia and have identified SOX17- and VEGF-R2-mediated signaling as the potential downstream pathways in its regulation of developmental coronary angiogenesis. RESULTS: HIF-1α stabilization by knocking out von Hippel Lindau (VHL) protein in the myocardium (cKO) disrupted normal coronary angiogenesis in embryonic mouse hearts, resembling patterns of accelerated coronary growth. VEGF-R2 expression was increased in coronary endothelial cells under hypoxia in vitro and in VHL cKO hearts in vivo. Similarly, SOX17 expression was increased in the VHL cKO hearts, while its knockout in the endocardium disrupted normal coronary growth. CONCLUSION: These findings provide further evidence that hypoxia regulates developmental coronary growth potentially through VEGF-R2 and SOX17 pathways, shedding light on mechanisms of coronary vessel development.
foxe1 mutant zebrafish show indications of a hypothyroid phenotype and increased sensitivity to ethanol for craniofacial malformations.
Raterman ST, Wagener FADTG, Zethof J … +4 more , Cuijpers V, Klaren PHM, Metz JR, Von den Hoff JW
Dev Dyn · 2025 Mar · PMID 39360443 · Full text
BACKGROUND: FOXE1 mutations in humans are associated with cleft palate and hypothyroidism. We previously developed a foxe1 mutant zebrafish demonstrating mineralization defects in larvae. In the present study, we investi...
BACKGROUND: FOXE1 mutations in humans are associated with cleft palate and hypothyroidism. We previously developed a foxe1 mutant zebrafish demonstrating mineralization defects in larvae. In the present study, we investigate the thyroid status and skeletal phenotype of adult foxe1 mutants. RESULTS: Mutant fish have increased expression of tshβ in the pituitary, and of hepatic dio1 and dio2. In plasma, we found higher Mg levels. Together these findings are indicative of hypothyroidism. We further observed mineralization defects in scales due to enhanced osteoclast activity as measured by increased expression levels of tracp, ctsk, and rankl. Gene-environment interactions in the etiology of FOXE1-related craniofacial abnormalities remain elusive, which prompts the need for models to investigate genotype-phenotype associations. We here investigated whether ethanol exposure increases the risk of developing craniofacial malformations in foxe1 mutant larvae that we compared to wild types. We found in ethanol-exposed mutants an increased incidence of developmental malformations and marked changes in gene expression patterns of cartilage markers (sox9a), apoptotic markers (casp3b), retinoic acid metabolism (cyp26c1), and tissue hypoxia markers (hifaa, hifab). CONCLUSION: Taken together, this study shows that the foxe1 mutant zebrafish recapitulates phenotypes associated with FOXE1 mutations in human patients and a clear foxe1-ethanol interaction.
Analysis of Meis2 knockout mice reveals Sonic hedgehog-mediated patterning of the cochlear duct.
Koo HY, Oh JH, Durán Alonso MB … +8 more , Hernández IL, González-Vallinas M, Alonso MT, Tena JJ, Gil-Gálvez A, Giraldez F, Bok J, Schimmang T
Dev Dyn · 2025 Apr · PMID 39351969 · Publisher ↗
BACKGROUND: The mechanisms underlying the formation of complex structures such as during the outgrowth of the cochlear duct are still poorly understood. RESULTS: We have analyzed the morphological and molecular changes a...
BACKGROUND: The mechanisms underlying the formation of complex structures such as during the outgrowth of the cochlear duct are still poorly understood. RESULTS: We have analyzed the morphological and molecular changes associated with cochlear development in mouse mutants for the transcription factor Meis2, which show defective coiling of the cochlea. These morphological abnormalities were accompanied by the formation of ectopic and extra rows of sensory hair cells. Gene profiling of otic vesicles from Meis2 mutants revealed a dysregulation of genes that are potentially involved in Sonic hedgehog (Shh)-mediated patterning of the cochlear duct. Like in Shh mutants, Meis2 defective mice showed a loss of genes that are expressed in the apical part of the cochlear duct. CONCLUSIONS: Taken together, these data reveal that the loss of Meis2 leads to a phenotype that resembles Shh mutants, suggesting that Meis2 is instrumental for cochlear Shh signaling. The modulation of the same subset of genes provides an interesting insight into which Shh responsive genes are essential for outgrowth and patterning of the cochlear duct.
Patterns of early embryogenesis and growth in the olfactory system of chick (Gallus gallus domesticus) based on iodine-enhanced micro-computed tomography.
Hogan AVC, Cerio DG, Bever GS
Dev Dyn · 2025 Apr · PMID 39344770 · Publisher ↗
BACKGROUND: The vertebrate olfactory system entails a complex set of neural/support structures that bridge morphogenetic regions. The developmental mechanisms coordinating this bridge remain unclear, even for model organ...
BACKGROUND: The vertebrate olfactory system entails a complex set of neural/support structures that bridge morphogenetic regions. The developmental mechanisms coordinating this bridge remain unclear, even for model organisms such as chick, Gallus gallus. Here, we combine previous growth data on the chick olfactory apparatus with new samples targeting its early embryogenesis. The purpose is to illuminate how early developmental dynamics integrate with scaling relationships to produce adult form and, potentially, evolutionary patterns. Olfactory structures, including epithelium, turbinate, nerve, and olfactory bulb, are considered in the context of neighboring nasal and brain structures. RESULTS: Axonal outgrowth from the olfactory epithelium, which eventually connects receptor neurons with the brain, begins earlier than previously established. This dynamic marks the beginning of a complex pattern of early differential growth wherein the olfactory bulbs scale with positive allometry relative to both brain volume and turbinate area, which in turn scale isometrically with one another. CONCLUSIONS: The mechanisms driving observed patterns of organogenesis and growth remain unclear awaiting experimental evidence. We discuss competing hypotheses, including the possibility that broad-based isometry of olfactory components reflects constraints imposed by high levels of functional/structural integration. Such integration would include the frontonasal prominence having a strong influence on telencephalic patterning.
Knockout of rbm24a and rbm24b genes in zebrafish impairs skeletal and cardiac muscle integrity and function during development.
Saquet A, Ying Z, Shi DL … +1 more , Grifone R
Dev Dyn · 2025 May · PMID 39323318 · Full text
BACKGOUND: Skeletal and cardiac muscles are contractile tissues whose development and function are dependent on genetic programs that must be precisely orchestrated in time and space. In addition to transcription factors...
BACKGOUND: Skeletal and cardiac muscles are contractile tissues whose development and function are dependent on genetic programs that must be precisely orchestrated in time and space. In addition to transcription factors, RNA-binding proteins tightly regulate gene expression by controlling the fate of RNA transcripts, thus specific proteins levels within the cell. Rbm24 has been identified as a key player of myogenesis and cardiomyogenesis in several vertebrates, by controlling various aspects of post-transcriptional regulation, including pre-mRNA alternative splicing and mRNA stabilization. In zebrafish, knockdown of rbm24a or rbm24b also causes skeletal and cardiac muscle phenotypes, but how their combined loss affects muscle integrity and function remains elusive. RESULTS: By genome editing, we have generated rbm24a and rbm24b single mutants as well as double mutants. Structural analyses indicate that homozygous rbm24a and rbm24b double mutants exhibit severe somitic muscle and cardiac phenotypes, although rbm24b single mutants are obviously normal. We further show that the loss of rbm24a and rbm24b disrupts sarcomere organization, impairing functional contractility and motility of skeletal and cardiac muscles. CONCLUSION: The rbm24 mutant zebrafish represents a new genetic tool for in-depth studies of Rbm24-mediated post-transcriptional regulation of skeletal and cardiac muscle development, disease and regeneration.
Expression analysis of genes including Zfhx4 in mice and zebrafish reveals a temporospatial conserved molecular basis underlying craniofacial development.
Liu S, Xu L, Kashima M … +14 more , Narumi R, Takahata Y, Nakamura E, Shibuya H, Tamura M, Shida Y, Inubushi T, Nukada Y, Miyazawa M, Hata K, Nishimura R, Yamashiro T, Tasaki J, Kurosaka H
Dev Dyn · 2025 Mar · PMID 39320016 · Full text
BACKGROUND: Embryonic craniofacial development involves several cellular and molecular events that are evolutionarily conserved among vertebrates. Vertebrate models such as mice and zebrafish have been used to investigat...
BACKGROUND: Embryonic craniofacial development involves several cellular and molecular events that are evolutionarily conserved among vertebrates. Vertebrate models such as mice and zebrafish have been used to investigate the molecular and cellular etiologies underlying human craniofacial disorders, including orofacial clefts. However, the molecular mechanisms underlying embryonic development in these two species are unknown. Therefore, elucidating the shared mechanisms of craniofacial development between disease models is crucial to understanding the underlying mechanisms of phenotypes in individual species. RESULTS: We selected mice and zebrafish as model organisms to compare various events during embryonic craniofacial development. We identified genes (Sox9, Zfhx3 and 4, Cjun, and Six1) exhibiting similar temporal expression patterns between these species through comprehensive and stage-matched gene expression analyses. Expression analysis revealed similar gene expression in hypothetically corresponding tissues, such as the mice palate and zebrafish ethmoid plate. Furthermore, loss-of-function analysis of Zfhx4/zfhx4, a causative gene of human craniofacial anomalies including orofacial cleft, in both species resulted in deformed skeletal elements such as the palatine and ethmoid plate in mice and zebrafish, respectively. CONCLUSIONS: These results demonstrate that these disease models share common molecular mechanisms, highlighting their usefulness in modeling craniofacial defects in humans.
Ventral body wall closure: Mechanistic insights from mouse models and translation to human pathology.
Formstone C, Aldeiri B, Davenport M … +1 more , Francis-West P
Dev Dyn · 2025 Feb · PMID 39319771 · Full text
The ventral body wall (VBW) that encloses the thoracic and abdominal cavities arises by extensive cell movements and morphogenetic changes during embryonic development. These morphogenetic processes include embryonic fol...
The ventral body wall (VBW) that encloses the thoracic and abdominal cavities arises by extensive cell movements and morphogenetic changes during embryonic development. These morphogenetic processes include embryonic folding generating the primary body wall; the initial ventral cover of the embryo, followed by directed mesodermal cell migrations, contributing to the secondary body wall. Clinical anomalies in VBW development affect approximately 1 in 3000 live births. However, the cell interactions and critical cellular behaviors that control VBW development remain little understood. Here, we describe the embryonic origins of the VBW, the cellular and morphogenetic processes, and key genes, that are essential for VBW development. We also provide a clinical overview of VBW anomalies, together with environmental and genetic influences, and discuss the insight gained from over 70 mouse models that exhibit VBW defects, and their relevance, with respect to human pathology. In doing so we propose a phenotypic framework for researchers in the field which takes into account the clinical picture. We also highlight cases where there is a current paucity of mouse models for particular clinical defects and key gaps in knowledge about embryonic VBW development that need to be addressed to further understand mechanisms of human VBW pathologies.
BMP signaling pathway member expression is enriched in enteric neural progenitors and required for zebrafish enteric nervous system development.
Moore JA, Moreno-Campos R, Noah AS … +2 more , Singleton EW, Uribe RA
Dev Dyn · 2025 Mar · PMID 39297504 · Full text
BACKGROUND: The vertebrate enteric nervous system (ENS) consists of a series of interconnected ganglia within the gastrointestinal (GI) tract, formed during development following migration of enteric neural crest cells (...
BACKGROUND: The vertebrate enteric nervous system (ENS) consists of a series of interconnected ganglia within the gastrointestinal (GI) tract, formed during development following migration of enteric neural crest cells (ENCCs) into the primitive gut tube. Much work has been done to unravel the complex nature of extrinsic and intrinsic factors that regulate processes that direct migration, proliferation, and differentiation of ENCCs. However, ENS development is a complex process, and we still have much to learn regarding the signaling factors that regulate ENCC development. RESULTS: Here in zebrafish, through transcriptomic, in situ transcript expression, immunohistochemical analysis, and chemical attenuation, we identified a time-dependent role for bone morphogenetic protein (BMP) in the maintenance of Phox2bb enteric progenitor numbers and/or time of differentiation of the progenitor pool. In support of our in silico transcriptomic analysis, we identified expression of a novel ENS ligand-encoding transcript, bmp5, within developmental regions of ENCCs. Through generation of a novel mutant bmp5 and bmp5 crispants, we identified a functional role for BMP5 in proper GI tract colonization, whereby phox2bb enteric progenitor numbers were reduced. CONCLUSION: Altogether, this work identified time-dependent roles for BMP signaling and a novel extrinsic factor, BMP5, that is necessary for vertebrate ENS formation.
Stage-by-stage exploration of normal embryonic development in the Arabian killifish, Aphanius dispar.
Alsakran A, Minhas R, Hamied AS … +3 more , Wilson RW, Ramsdale M, Kudoh T
Dev Dyn · 2025 May · PMID 39297499 · Full text
BACKGROUND: Arabian killifish, Aphanius dispar, lives in marine coastal areas of the Middle East, as well as in streams that experience a wide range of salinities and temperatures. It has been used as a mosquito control...
BACKGROUND: Arabian killifish, Aphanius dispar, lives in marine coastal areas of the Middle East, as well as in streams that experience a wide range of salinities and temperatures. It has been used as a mosquito control agent and for studying the toxicities of environmental pollutants. A. dispar's eggshell (chorion) and embryos are highly transparent and are suitable for high resolution microscopic observations, offering excellent visibility of live tissues. RESULTS: In this study, the staging of normal embryonic development of A. dispar was described and investigated at different temperatures. Embryonic development was then examined under different thermal environments from 26 to 34°C. Our data suggest that temperature has a significant effect on embryonic development, with accelerated development at higher temperatures. CONCLUSION: A. dispar exhibits broad thermal tolerance and extended independent feeding capabilities, making it a promising model organism for toxicology and pathogenesis studies conducted over an extended period of time (12 days post-fertilization).
Effects of life history strategies and habitats on limb regeneration in plethodontid salamanders.
Bothe V, Müller H, Shubin N … +1 more , Fröbisch N
Dev Dyn · 2025 May · PMID 39301774 · Full text
BACKGROUND: Salamanders are the only tetrapods that exhibit the ability to fully regenerate limbs. The axolotl, a neotenic salamander, has become the model organism for regeneration research. Great advances have been mad...
BACKGROUND: Salamanders are the only tetrapods that exhibit the ability to fully regenerate limbs. The axolotl, a neotenic salamander, has become the model organism for regeneration research. Great advances have been made providing a detailed understanding of the morphological and molecular processes involved in limb regeneration. However, it remains largely unknown how limb regeneration varies across salamanders and how factors like variable life histories, ecologies, and limb functions have influenced and shaped regenerative capacities throughout evolution. RESULTS: This study focuses on six species of plethodontid salamanders representing distinct life histories and habitats. Specimens were examined for regeneration ability after bite injuries as well as after controlled amputations. Morphological investigations revealed great regenerative abilities in all investigated species and frequent anatomical limb anomalies. Correlations were observed with respect to speed of regeneration and habitat. CONCLUSIONS: Investigating regeneration in non-model salamander taxa is essential for disentangling shared features of the regeneration process versus those that may be more taxon-specific. Gaining insights into variable aspects of regeneration under natural conditions and after conspecific biting rather than controlled amputations adds important new datapoints for understanding the evolutionary framework of regeneration and provides a broader context for interpreting findings made in the model organism axolotl.
Developmental cochlear defects are involved in early-onset hearing loss in A/J mice.
Kui L, Ma P, Zhao W … +6 more , Yan B, Kuang X, Li B, Geng R, Zheng T, Zheng Q
Dev Dyn · 2025 May · PMID 39291400 · Publisher ↗
BACKGROUND: A/J mice exhibited a severe hearing loss (HL) at juvenile stage. Up-to-date, studies on HL in A/J mice have mostly focused on the damage or dysfunction of hair cells (HCs), spiral ganglion neurons (SGNs), and...
BACKGROUND: A/J mice exhibited a severe hearing loss (HL) at juvenile stage. Up-to-date, studies on HL in A/J mice have mostly focused on the damage or dysfunction of hair cells (HCs), spiral ganglion neurons (SGNs), and stereocilia. We examined A/J mice at the early postnatal stage and found that the damage and the loss of outer hair cells (OHCs) are not severe enough to explain the profound HL observed at this age, which suggests that other cochlear defects may be responsible for HL. To better understand the mechanisms of early-onset HLin A/J mice, we characterized the pathology of the cochlea from postnatal day 3 to day 21. RESULTS: Our results showed defects in cochlear HC stereocilia and MET channel function as early as 3 days old. We also found abnormal localization and a significant reduction in the number of ribbon synapses in 2-week-old A/J mice. There are also abnormalities in the cochlear nerve innervation and terminal swellings in 3-week-old A/J mice. CONCLUSION: All of the abnormalities of cochlear existed in the A/J mice were identified in the juvenile stage and occurred before HCs or auditory nerve loss and was the initial pathological change. Our results suggest that developmental defects and subsequent cochlear degeneration are responsible for early-onset hearing loss in A/J mice.
Emerging biological functions of Twist1 in cell differentiation.
Tu M, Ge B, Li J … +11 more , Pan Y, Zhao B, Han J, Wu J, Zhang K, Liu G, Hou M, Yue M, Han X, Sun T, An Y
Dev Dyn · 2025 Jan · PMID 39254141 · Publisher ↗
Twist1 is required for embryonic development and expresses after birth in mesenchymal stem cells derived from mesoderm, where it governs mesenchymal cell development. As a well-known regulator of epithelial-mesenchymal t...
Twist1 is required for embryonic development and expresses after birth in mesenchymal stem cells derived from mesoderm, where it governs mesenchymal cell development. As a well-known regulator of epithelial-mesenchymal transition or embryonic organogenesis, Twist1 is important in a variety of developmental systems, including mesoderm formation, neurogenesis, myogenesis, cranial neural crest cell migration, and differentiation. In this review, we first highlight the physiological significance of Twist1 in cell differentiation, including osteogenic, chondrogenic, and myogenic differentiation, and then detail its probable molecular processes and signaling pathways. On this premise, we summarize the significance of Twist1 in distinct developmental disorders and diseases to provide a reference for studies on cell differentiation/development-related diseases.
Developmental ecology in embryos of an estuarine pupfish endemic of the Yucatan peninsula: Survival out of water, metabolic depression, and asynchronous hatching.
Domínguez-Castanedo O, Valdez-Carbajal S
Dev Dyn · 2025 Jan · PMID 39166847 · Publisher ↗
BACKGROUND: Theory predicts that drought-resistant embryos with extended incubations are evolutionarily favored in environments with high mortality of larvae but safe for eggs. Here, we experimentally test, under common...
BACKGROUND: Theory predicts that drought-resistant embryos with extended incubations are evolutionarily favored in environments with high mortality of larvae but safe for eggs. Here, we experimentally test, under common garden conditions, the effect of three incubation temperatures and media on embryonic developmental length, extended incubation out of the water, survival, metabolic rate, and hatching dynamics in the estuarine pupfish Garmanella pulchra. We also described the morphological changes of embryonic cortical structures related to air exposure. RESULTS: We found that embryos incubated out of water in low and medium temperatures present an extended incubation period beyond their hatching capability with a deep metabolic depression. Also, these embryos exhibited a hatching asynchrony not related to water availability. Embryos incubated at high temperatures did not show extended incubation, with decreased probability of survival out of water. Our morphological observations of the embryonic cortical structures reveal that the perivitelline space and hair-like filaments buffer the deleterious drought effects. CONCLUSIONS: Our results reveal that G. pulchra possesses life-history traits typical of two separate phenomena: delay hatching and diapause; supporting a true continuum between them, rather than a dichotomy. The evolution of these traits may respond to aerial exposure during low tides in the estuaries of Yucatán they inhabit.
Increased Netrin downstream of overactive Hedgehog signaling disrupts optic fissure formation.
Lusk S, LaPotin S, Presnell JS … +1 more , Kwan KM
Dev Dyn · 2025 Feb · PMID 39166841 · Full text
BACKGROUND: Uveal coloboma, a developmental eye defect, is caused by failed development of the optic fissure, a ventral structure in the optic stalk and cup where axons exit the eye and vasculature enters. The Hedgehog (...
BACKGROUND: Uveal coloboma, a developmental eye defect, is caused by failed development of the optic fissure, a ventral structure in the optic stalk and cup where axons exit the eye and vasculature enters. The Hedgehog (Hh) signaling pathway regulates optic fissure development: loss-of-function mutations in the Hh receptor ptch2 produce overactive Hh signaling and can result in coloboma. We previously proposed a model where overactive Hh signaling disrupts optic fissure formation by upregulating transcriptional targets acting both cell- and non-cell-autonomously. Here, we examine the Netrin family of secreted ligands as candidate Hh target genes. RESULTS: We find multiple Netrin ligands upregulated in the zebrafish ptch2 mutant during optic fissure development. Using a gain-of-function approach to overexpress Netrin in a spatiotemporally specific manner, we find that netrin1a or netrin1b overexpression is sufficient to cause coloboma and disrupt wild-type optic fissure formation. We used loss-of-function alleles, CRISPR/Cas9 mutagenesis, and morpholino knockdown to test if loss of Netrin can rescue coloboma in the ptch2 mutant: loss of netrin genes does not rescue the ptch2 mutant phenotype. CONCLUSION: These results suggest that Netrin is sufficient but not required to disrupt optic fissure formation downstream of overactive Hh signaling in the ptch2 mutant.
Hydrocortisone treatment as a tool to study conjunctival placode induction.
Drake PM, Franz-Odendaal TA
Dev Dyn · 2025 Jan · PMID 39096180 · Full text
BACKGROUND: Conjunctival placodes are a series of placodes that develop into the conjunctival (scleral) papillae and ultimately induce a series of scleral ossicles in the eyes of many vertebrates. This study establishes...
BACKGROUND: Conjunctival placodes are a series of placodes that develop into the conjunctival (scleral) papillae and ultimately induce a series of scleral ossicles in the eyes of many vertebrates. This study establishes a hydrocortisone injection procedure (incl. dosage) that consistently inhibits all conjunctival papillae in the embryonic chicken eye. The effects of this hydrocortisone treatment on apoptosis, vasculature, and placode-related gene expression were assessed. RESULTS: Hydrocortisone treatment does not increase apoptotic cell death or have a major effect on the ciliary artery or vascular plexus in the eye. β-catenin and Eda expression levels were not significantly altered following hydrocortisone treatment, despite the absence of conjunctival papillae. Notably, Fgf20 expression was significantly reduced following hydrocortisone treatment, and the distribution of β-catenin was altered. CONCLUSIONS: Our study showed that conjunctival papillae induction begins as early as HH27.5 (E5.5). Hydrocortisone treatment reduces Fgf20 expression independently of β-catenin and Eda and may instead affect other members of the Wnt/β-catenin or Eda/Edar pathways, or it may affect the ability of morphogens to diffuse through the extracellular matrix. This study contributes to a growing profile of gene expression data during placode development and enhances our understanding of how some vertebrate eyes develop these fascinating bones.
Modulation of mechanosensitive genes during embryonic aortic arch development.
Siddiqui HB, Golcez T, Çelik M … +6 more , Sevgin B, Çoban M, Süder İ, Kaya Ö, Özören N, Pekkan K
Dev Dyn · 2025 Mar · PMID 39096177 · Full text
BACKGROUND: Early embryonic aortic arches (AA) are a dynamic vascular structures that are in the process of shaping into the great arteries of cardiovascular system. Previously, a time-lapsed mechanosensitive gene expres...
BACKGROUND: Early embryonic aortic arches (AA) are a dynamic vascular structures that are in the process of shaping into the great arteries of cardiovascular system. Previously, a time-lapsed mechanosensitive gene expression map was established for AA subject to altered mechanical loads in the avian embryo. To validate this map, we investigated effects on vascular microstructure and material properties following the perturbation of key genes using an in-house microvascular gene knockdown system. RESULTS: All siRNA vectors show a decrease in the expression intensity of desired genes with no significant differences between vectors. In TGFβ3 knockdowns, we found a reduction in expression intensities of TGFβ3 (≤76%) and its downstream targets such as ELN (≤99.6%), Fbn1 (≤60%), COL1 (≤52%) and COL3 (≤86%) and an increase of diameter in the left AA (23%). MMP2 knockdown also reduced expression levels in MMP2 (≤30%) and a 6-fold increase in its downstream target COL3 with a decrease in stiffness of the AA wall and an increase in the diameter of the AA (55%). These in vivo measurements were confirmed using immunohistochemistry, western blotting and a computational growth model of the vascular extracellular matrix (ECM). CONCLUSIONS: Localized spatial genetic modification of the aortic arch region governs the vascular phenotype and ECM composition of the embryo and can be integrated with mechanically-induced congenital heart disease models.
Transcription factor Meis1b regulates craniofacial morphogenesis in zebrafish.
Psutkova V, Nickl P, Brezinova V … +2 more , Machonova O, Machon O
Dev Dyn · 2025 Jan · PMID 39087648 · Publisher ↗
BACKGROUND: Meis family of transcription factors operates in Pbx-Meis-Hox regulatory network controlling development of various tissues including eye, limbs, heart, hindbrain or craniofacial skeletal elements originating...
BACKGROUND: Meis family of transcription factors operates in Pbx-Meis-Hox regulatory network controlling development of various tissues including eye, limbs, heart, hindbrain or craniofacial skeletal elements originating from the neural crest. Although studies in mouse provide abundant information about Meis factors function in embryogenesis, little is known about their role in zebrafish. RESULTS: We generated zebrafish lines carrying null mutations in meis1a, meis1b, meis2a, and meis2b genes. Only meis1b mutants are lethal at larval stage around 13 dpf whereas the other mutant lines are viable and fertile. We focused on development of neural crest-derived craniofacial structures such as tendons, cranial nerves, cartilage and accompanying muscles. Meis1b mutants displayed morphogenetic abnormalities in the cartilage originating from the first and second pharyngeal arches. Meckel's cartilage was shorter and wider with fused anterior symphysis and abnormal chondrocyte organization. This resulted in impaired tendons and muscle fiber connections while tenocyte development was not largely affected. CONCLUSIONS: Loss-of-function mutation in meis1b affects cartilage morphology in the lower jaw that leads to disrupted organization of muscles and tendons.
Disruption of the creb3l1 gene causes defects in caudal fin regeneration and patterning in zebrafish Danio rerio.
VanWinkle PE, Lee E, Wynn B … +6 more , Nawara TJ, Thomas H, Parant J, Alvarez C, Serra R, Sztul E
Dev Dyn · 2024 Dec · PMID 39003620 · Full text
BACKGROUND: The gene cAMP-Responsive Element Binding protein 3-like-1 (CREB3L1) has been implicated in bone development in mice, with CREB3L1 knock-out mice exhibiting fragile bones, and in humans, with CREB3L1 mutations...
BACKGROUND: The gene cAMP-Responsive Element Binding protein 3-like-1 (CREB3L1) has been implicated in bone development in mice, with CREB3L1 knock-out mice exhibiting fragile bones, and in humans, with CREB3L1 mutations linked to osteogenesis imperfecta. However, the mechanism through which Creb3l1 regulates bone development is not fully understood. RESULTS: To probe the role of Creb3l1 in organismal physiology, we used CRISPR-Cas9 genome editing to generate a Danio rerio (zebrafish) model of Creb3l1 deficiency. In contrast to mammalian phenotypes, the Creb3l1 deficient fish do not display abnormalities in osteogenesis, except for a decrease in the bifurcation pattern of caudal fin. Both, skeletal morphology and overall bone density appear normal in the mutant fish. However, the regeneration of caudal fin postamputation is significantly affected, with decreased overall regenerate and mineralized bone area. Moreover, the mutant fish exhibit a severe patterning defect during regeneration, with a significant decrease in bifurcation complexity of the fin rays and distalization of the bifurcation sites. Analysis of genes implicated in bone development showed aberrant patterning of shha and ptch2 in Creb3l1 deficient fish, linking Creb3l1 with Sonic Hedgehog signaling during fin regeneration. CONCLUSIONS: Our results uncover a novel role for Creb3l1 in regulating tissue growth and patterning during regeneration.
BMP4 regulates asymmetric Pkd2 distribution in mouse nodal immotile cilia and ciliary mechanosensing required for left-right determination.
Katoh TA, Lange T, Nakajima Y … +3 more , Yashiro K, Okada Y, Hamada H
Dev Dyn · 2025 Aug · PMID 38984461 · Full text
BACKGROUND: Mouse nodal immotile cilia mechanically sense the bending direction for left-right (L-R) determination and activate the left-side-specific signaling cascade, leading to increased Nodal activity. Asymmetric di...
BACKGROUND: Mouse nodal immotile cilia mechanically sense the bending direction for left-right (L-R) determination and activate the left-side-specific signaling cascade, leading to increased Nodal activity. Asymmetric distribution of Pkd2, a crucial channel for L-R determination, on immotile cilia has been reported recently. However, the causal relationship between the asymmetric Pkd2 distribution and direction-dependent flow sensing is not well understood. Furthermore, the underlying molecular mechanism directing this asymmetric Pkd2 distribution remains unclear. RESULTS: The effects of several recombinant proteins and inhibitors on the Pkd2 distribution were analyzed using super-resolution microscopy. Notably, bone morphogenetic protein 4 (BMP4) affected the Pkd2 distribution. Additionally, three-dimensional manipulation of nodal immotile cilia using optical tweezers revealed that excess BMP4 caused defects in the mechanosensing ability of the cilia. CONCLUSIONS: Experimental data together with model calculations suggest that BMP4 regulates the asymmetric distribution of Pkd2 in nodal immotile cilia, thereby affecting the ability of these cilia to sense the bending direction for L-R determination. This study, for the first time, provides insight into the relationship between the asymmetric protein distribution in cilia and their function.
Actin cytoskeletal regulation of ciliogenesis in development and disease.
Hufft-Martinez BM, Wang HH, Saadi I … +1 more , Tran PV
Dev Dyn · 2024 Dec · PMID 38958410 · Full text
Primary cilia are antenna-like sensory organelles that are evolutionarily conserved in nearly all modern eukaryotes, from the single-celled green alga, Chlamydomonas reinhardtii, to vertebrates and mammals. Cilia are mic...
Primary cilia are antenna-like sensory organelles that are evolutionarily conserved in nearly all modern eukaryotes, from the single-celled green alga, Chlamydomonas reinhardtii, to vertebrates and mammals. Cilia are microtubule-based cellular projections that have adapted to perform a broad range of species-specific functions, from cell motility to detection of light and the transduction of extracellular mechanical and chemical signals. These functions render cilia essential for organismal development and survival. The high conservation of cilia has allowed for discoveries in C. reinhardtii to inform our understanding of the basic biology of mammalian primary cilia, and to provide insight into the genetic etiology of ciliopathies. Over the last two decades, a growing number of studies has revealed that multiple aspects of ciliary homeostasis are regulated by the actin cytoskeleton, including centrosome migration and positioning, vesicle transport to the basal body, ectocytosis, and ciliary-mediated signaling. Here, we review actin regulation of ciliary homeostasis, and highlight conserved and divergent mechanisms in C. reinhardtii and mammalian cells. Further, we compare the disease manifestations of patients with ciliopathies to those with mutations in actin and actin-associated genes, and propose that primary cilia defects caused by genetic alteration of the actin cytoskeleton may underlie certain birth defects.
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