scholarly journals Ectopic Hedgehog Signaling Causes Cleft Palate and Defective Osteogenesis

2018 ◽  
Vol 97 (13) ◽  
pp. 1485-1493 ◽  
Author(s):  
N.L. Hammond ◽  
K.J. Brookes ◽  
M.J. Dixon
Keyword(s):  
Cleft Palate ◽  
Hedgehog Signaling ◽  
Regulatory Networks ◽  
Neural Crest Cell ◽  
Bmp Signaling ◽  
The Novel ◽  
Morphogenetic Protein ◽  
Secondary Palate ◽  
Hh Signaling ◽  
Crest Cell

Cleft palate is a common birth defect that frequently occurs in human congenital malformations caused by mutations in components of the Sonic Hedgehog (S HH) signaling cascade. Shh is expressed in dynamic, spatiotemporal domains within epithelial rugae and plays a key role in driving epithelial-mesenchymal interactions that are central to development of the secondary palate. However, the gene regulatory networks downstream of Hedgehog (Hh) signaling are incompletely characterized. Here, we show that ectopic Hh signaling in the palatal mesenchyme disrupts oral-nasal patterning of the neural crest cell–derived ectomesenchyme of the palatal shelves, leading to defective palatine bone formation and fully penetrant cleft palate. We show that a series of Fox transcription factors, including the novel direct target Foxl1, function downstream of Hh signaling in the secondary palate. Furthermore, we demonstrate that Wnt/bone morphogenetic protein (BMP) antagonists, in particular Sostdc1, are positively regulated by Hh signaling, concomitant with downregulation of key regulators of osteogenesis and BMP signaling effectors. Our data demonstrate that ectopic Hh-Smo signaling downregulates Wnt/BMP pathways, at least in part by upregulating Sostdc1, resulting in cleft palate and defective osteogenesis.

scholarly journals Crucial and Overlapping Roles of Six1 and Six2 in Craniofacial Development

2019 ◽  
Vol 98 (5) ◽  
pp. 572-579 ◽  
Author(s):  
Z. Liu ◽  
C. Li ◽  
J. Xu ◽  
Y. Lan ◽  
H. Liu ◽  
...  
Keyword(s):  
Neural Crest ◽  
Ectopic Expression ◽  
Mandibular Condyle ◽  
Neural Crest Cell ◽  
Messenger Rnas ◽  
Developmental Defects ◽  
Facial Cleft ◽  
Frontonasal Dysplasia ◽  
Morphogenetic Protein ◽  
Crest Cell

SIX1 and SIX2 encode closely related transcription factors of which disruptions have been associated with distinct craniofacial syndromes, with mutations in SIX1 associated with branchiootic syndrome 3 (BOS3) and heterozygous deletions of SIX2 associated with frontonasal dysplasia defects. Whereas mice deficient in Six1 recapitulated most of the developmental defects associated with BOS3, mice lacking Six2 function had no obvious frontonasal defects. We show that Six1 and Six2 exhibit partly overlapping patterns of expression in the developing mouse embryonic frontonasal, maxillary, and mandibular processes. We found that Six1 –/– Six2 –/– double-mutant mice were born with severe craniofacial deformity not seen in the Six1 –/– or Six2 –/– single mutants, including skull bone agenesis, midline facial cleft, and syngnathia. Moreover, whereas Six1 –/– mice exhibited partial transformation of maxillary zygomatic bone into a mandibular condyle-like structure, Six1 –/–Six2 +/– mice exhibit significantly increased penetrance of the maxillary malformation. In addition to ectopic Dlx5 expression at the maxillary-mandibular junction as recently reported in E10.5 Six1 –/– embryos, the E10.5 Six1 –/– Six2 +/– embryos showed ectopic expression of Bmp4, Msx1, and Msx2 messenger RNAs in the maxillary-mandibular junction. Genetically inactivating 1 allele of either Ednra or Bmp4 significantly reduced the penetrance of maxillary malformation in both Six1 –/– and Six1 –/– Six2 +/– embryos, indicating that Six1 and Six2 regulate both endothelin and bone morphogenetic protein-4 signaling pathways to pattern the facial structures. Furthermore, we show that neural crest–specific inactivation of Six1 in Six2 –/– embryos resulted in midline facial cleft and frontal bone agenesis. We show that Six1 –/– Six2 –/– embryos exhibit significantly reduced expression of key frontonasal development genes Alx1 and Alx3 as well as increased apoptosis in the developing frontonasal mesenchyme. Together, these results indicate that Six1 and Six2 function partly redundantly to control multiple craniofacial developmental processes and play a crucial neural crest cell–autonomous role in frontonasal morphogenesis.

scholarly journals BMP signaling is necessary for neural crest cell migration and ganglion formation in the enteric nervous system

2005 ◽  
Vol 122 (6) ◽  
pp. 821-833 ◽  
Author(s):  
Allan M. Goldstein ◽  
Katherine C. Brewer ◽  
Adele M. Doyle ◽  
Nandor Nagy ◽  
Drucilla J. Roberts
Keyword(s):  
Nervous System ◽  
Cell Migration ◽  
Neural Crest ◽  
Enteric Nervous System ◽  
Neural Crest Cell ◽  
Bmp Signaling ◽  
Neural Crest Cell Migration ◽  
Crest Cell

scholarly journals Metalloprotease-Dependent Attenuation of BMP Signaling Restricts Cardiac Neural Crest Cell Fate

Cell Reports ◽  
2019 ◽  
Vol 29 (3) ◽  
pp. 603-616.e5
Author(s):  
Hiroyuki N. Arai ◽  
Fuminori Sato ◽  
Takuya Yamamoto ◽  
Knut Woltjen ◽  
Hiroshi Kiyonari ◽  
...  
Keyword(s):  
Neural Crest ◽  
Cell Fate ◽  
Neural Crest Cell ◽  
Bmp Signaling ◽  
Cardiac Neural Crest ◽  
Crest Cell

scholarly journals The novel ciliogenesis regulator DYRK2 governs Hedgehog signaling during mouse embryogenesis

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Saishu Yoshida ◽  
Katsuhiko Aoki ◽  
Ken Fujiwara ◽  
Takashi Nakakura ◽  
Akira Kawamura ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Primary Cilia ◽  
Molecular Mechanisms ◽  
The Novel ◽  
Mammalian Development ◽  
Hh Signaling ◽  
Functional Analyses ◽  
First Time ◽  
Insight Into

Mammalian Hedgehog (Hh) signaling plays key roles in embryogenesis and uniquely requires primary cilia. Functional analyses of several ciliogenesis-related genes led to the discovery of the developmental diseases known as ciliopathies. Hence, identification of mammalian factors that regulate ciliogenesis can provide insight into the molecular mechanisms of embryogenesis and ciliopathy. Here, we demonstrate that DYRK2 acts as a novel mammalian ciliogenesis-related protein kinase. Loss of Dyrk2 in mice causes suppression of Hh signaling and results in skeletal abnormalities during in vivo embryogenesis. Deletion of Dyrk2 induces abnormal ciliary morphology and trafficking of Hh pathway components. Mechanistically, transcriptome analyses demonstrate down-regulation of Aurka and other disassembly genes following Dyrk2 deletion. Taken together, the present study demonstrates for the first time that DYRK2 controls ciliogenesis and is necessary for Hh signaling during mammalian development.

scholarly journals Dexamethasone Suppresses Palatal Cell Proliferation through miR-130a-3p

2021 ◽  
Vol 22 (22) ◽  
pp. 12453
Author(s):  
Hiroki Yoshioka ◽  
Goo Jun ◽  
Akiko Suzuki ◽  
Junichi Iwata
Keyword(s):  
Cell Proliferation ◽  
Cleft Palate ◽  
Birth Defects ◽  
Cleft Lip ◽  
Neural Crest Cell ◽  
Congenital Birth Defects ◽  
Cranial Neural Crest Cell ◽  
Primary Mouse ◽  
Mirna Sequencing ◽  
Crest Cell

Cleft lip with or without cleft palate (CL/P) is one of the most common congenital birth defects. This study aims to identify novel pathogenic microRNAs associated with cleft palate (CP). Through data analyses of miRNA-sequencing for developing palatal shelves of C57BL/6J mice, we found that miR-449a-3p, miR-449a-5p, miR-449b, miR-449c-3p, and miR-449c-5p were significantly upregulated, and that miR-19a-3p, miR-130a-3p, miR-301a-3p, and miR-486b-5p were significantly downregulated, at embryonic day E14.5 compared to E13.5. Among them, overexpression of the miR-449 family (miR-449a-3p, miR-449a-5p, miR-449b, miR-449c-3p, and miR-449c-5p) and miR-486b-5p resulted in reduced cell proliferation in primary mouse embryonic palatal mesenchymal (MEPM) cells and mouse cranial neural crest cell line O9-1. On the other hand, inhibitors of miR-130a-3p and miR-301a-3p significantly reduced cell proliferation in MEPM and O9-1 cells. Notably, we found that treatment with dexamethasone, a glucocorticoid known to induce CP in mice, suppressed miR-130a-3p expression in both MEPM and O9-1 cells. Moreover, a miR-130a-3p mimic could ameliorate the cell proliferation defect induced by dexamethasone through normalization of Slc24a2 expression. Taken together, our results suggest that miR-130-3p plays a crucial role in dexamethasone-induced CP in mice.

scholarly journals Building the Border: Development of the Chordate Neural Plate Border Region and Its Derivatives

2020 ◽  
Vol 11 ◽  
Author(s):  
Ankita Thawani ◽  
Andrew K. Groves
Keyword(s):  
Neural Crest ◽  
Signaling Pathways ◽  
Regulatory Networks ◽  
Neural Plate ◽  
Bmp Signaling ◽  
Border Region ◽  
Thin Strip ◽  
Morphogenetic Protein ◽  
Neural Plate Border ◽  
Spatio Temporal

The paired cranial sensory organs and peripheral nervous system of vertebrates arise from a thin strip of cells immediately adjacent to the developing neural plate. The neural plate border region comprises progenitors for four key populations of cells: neural plate cells, neural crest cells, the cranial placodes, and epidermis. Putative homologues of these neural plate border derivatives can be found in protochordates such as amphioxus and tunicates. In this review, we summarize key signaling pathways and transcription factors that regulate the inductive and patterning events at the neural plate border region that give rise to the neural crest and placodal lineages. Gene regulatory networks driven by signals from WNT, fibroblast growth factor (FGF), and bone morphogenetic protein (BMP) signaling primarily dictate the formation of the crest and placodal lineages. We review these studies and discuss the potential of recent advances in spatio-temporal transcriptomic and epigenomic analyses that would allow a mechanistic understanding of how these signaling pathways and their downstream transcriptional cascades regulate the formation of the neural plate border region.

scholarly journals Molecular and Cellular Mechanisms of Palate Development

2017 ◽  
Vol 96 (11) ◽  
pp. 1184-1191 ◽  
Author(s):  
C. Li ◽  
Y. Lan ◽  
R. Jiang
Keyword(s):  
Growth Factor ◽  
Regulatory Networks ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cellular Mechanisms ◽  
Palate Development ◽  
Palatal Shelf ◽  
Cellular Processes ◽  
Morphogenetic Protein ◽  
Secondary Palate

Development of the mammalian secondary palate involves highly dynamic morphogenetic processes, including outgrowth of palatal shelves from the oral side of the embryonic maxillary prominences, elevation of the initially vertically oriented palatal shelves to the horizontal position above the embryonic tongue, and subsequently adhesion and fusion of the paired palatal shelves at the midline to separate the oral cavity from the nasal cavity. Perturbation of any of these processes could cause cleft palate, a common birth defect that significantly affects patients’ quality of life even after surgical treatment. In addition to identifying a large number of genes required for palate development, recent studies have begun to unravel the extensive cross-regulation of multiple signaling pathways, including Sonic hedgehog, bone morphogenetic protein, fibroblast growth factor, transforming growth factor β, and Wnt signaling, and multiple transcription factors during palatal shelf growth and patterning. Multiple studies also provide new insights into the gene regulatory networks and/or dynamic cellular processes underlying palatal shelf elevation, adhesion, and fusion. Here we summarize major recent advances and integrate the genes and molecular pathways with the cellular and morphogenetic processes of palatal shelf growth, patterning, elevation, adhesion, and fusion.

scholarly journals FGF and retinoic acid activity gradients control the timing of neural crest cell emigration in the trunk

2011 ◽  
Vol 194 (3) ◽  
pp. 489-503 ◽  
Author(s):  
Patricia L. Martínez-Morales ◽  
Ruth Diez del Corral ◽  
Isabel Olivera-Martínez ◽  
Alejandra C. Quiroga ◽  
Raman M. Das ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Neural Crest ◽  
Epithelial Mesenchymal Transition ◽  
Neural Crest Cell ◽  
Fibroblast Growth ◽  
Loss Of Function ◽  
Mesenchymal Transition ◽  
Morphogenetic Protein ◽  
Trunk Neural Crest ◽  
Crest Cell

Coordination between functionally related adjacent tissues is essential during development. For example, formation of trunk neural crest cells (NCCs) is highly influenced by the adjacent mesoderm, but the molecular mechanism involved is not well understood. As part of this mechanism, fibroblast growth factor (FGF) and retinoic acid (RA) mesodermal gradients control the onset of neurogenesis in the extending neural tube. In this paper, using gain- and loss-of-function experiments, we show that caudal FGF signaling prevents premature specification of NCCs and, consequently, premature epithelial–mesenchymal transition (EMT) to allow cell emigration. In contrast, rostrally generated RA promotes EMT of NCCs at somitic levels. Furthermore, we show that FGF and RA signaling control EMT in part through the modulation of elements of the bone morphogenetic protein and Wnt signaling pathways. These data establish a clear role for opposition of FGF and RA signaling in control of the timing of NCC EMT and emigration and, consequently, coordination of the development of the central and peripheral nervous system during vertebrate trunk elongation.

scholarly journals cdon and boc affect trunk neural crest cell migration through a non-cell autonomous reduction of hedgehog signaling in zebrafish slow-twitch muscle

2022 ◽  
Author(s):  
Ezra Lencer ◽  
Rytis Prekeris ◽  
Kristin Artinger
Keyword(s):  
Cell Migration ◽  
Neural Crest ◽  
Hedgehog Signaling ◽  
Neural Crest Cell ◽  
Vertebrate Development ◽  
Neural Crest Cell Migration ◽  
Slow Twitch Muscle ◽  
Slow Twitch ◽  
Neural Crest Migration ◽  
Crest Cell

The immunoglobin superfamily members cdon and boc are transmembrane proteins implicated in regulating hedgehog signaling during vertebrate development. Recent work showing roles for these genes in axon guidance and neural crest cell migration further suggest that cdon/boc may play additional functions in regulating directed cell movements during development. Here we use novel and existing mutants to investigate a role for cdon and boc in zebrafish neural crest cell migration. We find that single cdon or boc mutant embryos exhibit normal neural crest phenotypes, but that neural crest migration is strikingly disrupted in double cdon/boc mutant embryos. We further show that this neural crest migration phenotype is associated with defects to the differentiation of slow-twitch muscle cells, and that this slow-twitch muscle phenotype is a consequence of reduced hedgehog signaling in mutant fish. While neural crest migratory ability is not affected in double mutant embryos, neural crest directionality is severely affected. These data suggest that neural crest migration defects are likely to be secondary to defects in slow-twitch muscle differentiation. Combined, our data add to a growing literature showing that cdon and boc act synergistically to promote hedgehog signaling during vertebrate development, and provide a foundation for using zebrafish to further study the function of these hedgehog receptor paralogs.

scholarly journals Roles of the Hedgehog Signaling Pathway in Skin Development, Homeostasis and Cancer

2017 ◽  
Author(s):  
Yoshinori Abe ◽  
Nobuyuki Tanaka
Keyword(s):  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Signaling Pathway ◽  
Basal Cell ◽  
Hedgehog Signaling ◽  
Current Knowledge ◽  
Skin Development ◽  
Morphogenetic Protein ◽  
Hh Signaling

The epidermis is the outermost layer of skin and provides a protective barrier against environmental insults. It is a rapidly renewing tissue undergoing constant regeneration, maintained by several types of stem cells. Hedgehog (HH) ligands activate one of the fundamental signaling pathways that contribute to epidermal development, homeostasis and repair. The HH pathway interacts with other signal transduction pathways such as those activated by Wnt and bone morphogenetic protein. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important to elucidate fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in skin development, homeostasis and basal cell carcinoma formation, providing an update of current knowledge in this field.

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