The role of bone morphogenetic proteins in vertebral development

Development ◽  
1996 ◽  
Vol 122 (11) ◽  
pp. 3607-3616 ◽  
Author(s):  
A.H. Monsoro-Burq ◽  
D. Duprez ◽  
Y. Watanabe ◽  
M. Bontoux ◽  
C. Vincent ◽  
...  
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Neural Tube ◽  
Molecular Mechanisms ◽  
Spinous Process ◽  
Expression Patterns ◽  
Neural Tube Closure ◽  
Dorsal Neural Tube ◽  
Negative Effect ◽  
Msx Genes ◽  
Cell Growth And Differentiation

This study first shows a striking parallel between the expression patterns of the Bmp4, Msx1 and Msx2 genes in the lateral ridges of the neural plate before neural tube closure and later on, in the dorsal neural tube and superficial midline ectoderm. We have previously shown that the spinous process of the vertebra is formed from Msx1- and 2-expressing mesenchyme and that the dorsal neural tube can induce the differentiation of subcutaneous cartilage from the somitic mesenchyme. We show here that mouse BMP4- or human BMP2-producing cells grafted dorsally to the neural tube at E2 or E3 increase considerably the amount of Msx-expressing mesenchymal cells which are normally recruited from the somite to form the spinous process of the vertebra. Later on, the dorsal part of the vertebra is enlarged, resulting in vertebral fusion and, in some cases (e.g. grafts made at E3), in the formation of a ‘giant’ spinous process-like structure dorsally. In strong contrast, BMP-producing cells grafted laterally to the neural tube at E2 exerted a negative effect on the expression of Pax1 and Pax3 genes in the somitic mesenchyme, which then turned on Msx genes. Moreover, sclerotomal cell growth and differentiation into cartilage were then inhibited. Dorsalization of the neural tube, manifested by expression of Msx and Pax3 genes in the basal plate contacting the BMP-producing cells, was also observed. In conclusion, this study demonstrates that differentiation of the ventrolateral and dorsal parts of the vertebral cartilage is controlled by different molecular mechanisms. The former develops under the influence of signals arising from the floor plate-notochord complex. These signals inhibit the development of dorsal subcutaneous cartilage forming the spinous process, which requires the influence of BMP4 to differentiate.

scholarly journals Effects of Shh and Noggin on neural crest formation demonstrate that BMP is required in the neural tube but not ectoderm

Development ◽  
1998 ◽  
Vol 125 (24) ◽  
pp. 4919-4930 ◽  
Author(s):  
M.A. Selleck ◽  
M.I. Garcia-Castro ◽  
K.B. Artinger ◽  
M. Bronner-Fraser
Keyword(s):  
Neural Crest ◽  
Sonic Hedgehog ◽  
Neural Tube ◽  
Neural Crest Cells ◽  
Neural Plate ◽  
Bmp Signaling ◽  
Neural Tube Closure ◽  
Dorsal Neural Tube ◽  
Neural Ectoderm ◽  
Tube Closure

To define the timing of neural crest formation, we challenged the fate of presumptive neural crest cells by grafting notochords, Sonic Hedgehog- (Shh) or Noggin-secreting cells at different stages of neurulation in chick embryos. Notochords or Shh-secreting cells are able to prevent neural crest formation at open neural plate levels, as assayed by DiI-labeling and expression of the transcription factor, Slug, suggesting that neural crest cells are not committed to their fate at this time. In contrast, the BMP signaling antagonist, Noggin, does not repress neural crest formation at the open neural plate stage, but does so if injected into the lumen of the closing neural tube. The period of Noggin sensitivity corresponds to the time when BMPs are expressed in the dorsal neural tube but are down-regulated in the non-neural ectoderm. To confirm the timing of neural crest formation, Shh or Noggin were added to neural folds at defined times in culture. Shh inhibits neural crest production at early stages (0-5 hours in culture), whereas Noggin exerts an effect on neural crest production only later (5-10 hours in culture). Our results suggest three phases of neurulation that relate to neural crest formation: (1) an initial BMP-independent phase that can be prevented by Shh-mediated signals from the notochord; (2) an intermediate BMP-dependent phase around the time of neural tube closure, when BMP-4 is expressed in the dorsal neural tube; and (3) a later pre-migratory phase which is refractory to exogenous Shh and Noggin.

scholarly journals Bone morphogenetic proteins regulate neural tube closure by interacting with the apicobasal polarity pathway

Development ◽  
2011 ◽  
Vol 138 (15) ◽  
pp. 3179-3188 ◽  
Author(s):  
D. S. Eom ◽  
S. Amarnath ◽  
J. L. Fogel ◽  
S. Agarwala
Keyword(s):  
Bone Morphogenetic Proteins ◽  
Neural Tube ◽  
Neural Tube Closure ◽  
Apicobasal Polarity ◽  
Tube Closure

scholarly journals BMP4 patterns Smad activity and generates stereotyped cell fate organisation in spinal organoids

2019 ◽  
Author(s):  
Nathalie Duval ◽  
Célia Vaslin ◽  
Tiago Barata ◽  
Stéphane Nédélec ◽  
Vanessa Ribes
Keyword(s):  
Cell Fate ◽  
Bone Morphogenetic Proteins ◽  
Neural Tube ◽  
Spatial Organization ◽  
Time Windows ◽  
Spatial Dynamics ◽  
Spatial Arrangement ◽  
Cell Types ◽  
Dorsal Neural Tube ◽  
Bmp Signalling

AbstractBone Morphogenetic Proteins (BMP) are secreted regulators of cell fate in several developing tissues. In the embryonic spinal cord, they control the emergence of the neural crest, roof plate and distinct subsets of dorsal interneurons. Although a gradient of BMP activity has been proposed to determine cell type identity in vivo, whether this is sufficient for pattern formation in vitro is unclear. Here, we demonstrate that exposure to BMP4 initiates distinct spatial dynamics of BMP signalling within the self-emerging epithelia of both mouse and human pluripotent stem cells derived spinal organoids. The pattern of BMP signalling results in the stereotyped spatial arrangement of dorsal neural tube cell types and concentration, timing and duration of BMP4 exposure modulate these patterns. Moreover, differences in the duration of competence time-windows between mouse and human account for the species specific tempo of neural differentiation. Together the study describes efficient methods to generate patterned subsets of dorsal interneurons in spinal organoids and supports the conclusion that graded BMP activity orchestrates the spatial organization of the dorsal neural tube cellular diversity in mouse and human.

Open brain, a new mouse mutant with severe neural tube defects, shows altered gene expression patterns in the developing spinal cord

Development ◽  
1994 ◽  
Vol 120 (11) ◽  
pp. 3119-3130 ◽  
Author(s):  
T. Gunther ◽  
M. Struwe ◽  
A. Aguzzi ◽  
K. Schughart
Keyword(s):  
Gene Expression ◽  
Spinal Cord ◽  
Dorsal Root Ganglia ◽  
Neural Tube ◽  
Dorsal Root ◽  
Expression Patterns ◽  
Axial Skeleton ◽  
Neural Tube Closure ◽  
Primary Defect ◽  
Developing Spinal Cord

We describe a new mouse mutation, designated open brain (opb), which results in severe defects in the developing neural tube. Homozygous opb embryos exhibited an exencephalic malformation involving the forebrain, midbrain and hindbrain regions. The primary defect of the exencephaly could be traced back to a failure to initiate neural tube closure at the midbrain-forebrain boundary. Severe malformations in the spinal cord and dorsal root ganglia were observed in the thoracic region. The spinal cord of opb mutant embryos exhibited an abnormal circular to oval shape and showed defects in both ventral and dorsal regions. In severely affected spinal cord regions, a dorsalmost region of cells negative for Wnt-3a, Msx-2, Pax-3 and Pax-6 gene expression was detected and dorsal expression of Pax-6 was increased. In ventral regions, the area of Shh and HNF-3 beta expression was enlarged and the future motor neuron horns appeared to be reduced in size. These observations indicate that opb embryos exhibit defects in the specification of cells along the dorsoventral axis of the developing spinal cord. Although small dorsal root ganglia were formed in opb mutants, their metameric organization was lost. In addition, defects in eye development and malformations in the axial skeleton and developing limbs were observed. The implications of these findings are discussed in the context of dorsoventral patterning of the developing neural tube and compared with known mouse mutants exhibiting similar defects.

scholarly journals MTRR gene variant rs1801394 found in Malaysian patients with neural tube defects

2020 ◽  
Vol 3 (1) ◽  
pp. 24-31
Author(s):  
Amelia Cheng Wei Tan ◽  
Siti Waheeda Mohd-Zin ◽  
Nur'Awatif Ishak ◽  
Meow-Keong Thong ◽  
Azlina Ahmad-Annuar ◽  
...  
Keyword(s):  
Neural Tube ◽  
Neural Tube Defects ◽  
Carbon Metabolism ◽  
Protein Function ◽  
Molecular Mechanisms ◽  
Protein Function Prediction ◽  
Neural Tube Closure ◽  
Nucleotide Polymorphisms ◽  
One Carbon Metabolism ◽  
The One

Neural tube defects (NTDs) are congenital anomalies resulting from the failure of neural tube closure during embryogenesis. The precise molecular mechanisms underlying this multifactorial disease is poorly understood, although single nucleotide polymorphisms in genes involved in the one-carbon metabolism cycle are believed to contribute towards NTD development. Among them is 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Protein function prediction algorithms (PolyPhen-2, PROVEAN, SIFT, SMART-Ensembl) were employed to evaluate its pathogenicity potential caused by the replacement of isoleucine with methionine. Seven NTD patients and 12 of their parents were recruited for this study. DNA samples were collected through blood or saliva whereby the extracted DNAs were then sent for whole exome sequencing (WES). Zygosity of the variant was confirmed from WES data of each subject and further validated through polymerase chain reaction (PCR) and Sanger sequencing. The results revealed that 57% of patients and 83% of parents carried rs1801394 mutation in their MTRR gene, based on either homozygous (G/G) or heterozygous (A/G) genotypes. Bioinformatics analysis of this missense mutation predicted that this change is damaging to MTRR protein function by 2 of the 3 predictor algorithms and that the change from isoleucine to methionine amino acid affects flavodoxin domain of the protein. This impacts enzyme activity within the one-carbon metabolism pathway, which is linked to the aetiology of NTDs. From population databases, this variant was considered common with a MAF >0.3, however, it was not found in the Singapore Genome Variation Project (SGVP), whose population is a closer representation of the Malaysian subjects investigated here. Hence, we explored the prevalence of this variant in other studies and found that its association with NTDs differed across populations worldwide. Finally, we conclude that rs1801394 may be an NTD risk factor in the Malaysian population and should be further investigated as a potential prenatal screening tool.

scholarly journals Scribble mutation disrupts convergent extension and apical constriction during mammalian neural tube closure

2020 ◽  
Author(s):  
Alyssa C. Lesko ◽  
Raymond Keller ◽  
Ping Chen ◽  
Ann Sutherland
Keyword(s):  
Neural Tube ◽  
Neural Development ◽  
Molecular Mechanisms ◽  
Neural Cell ◽  
Cytoskeletal Proteins ◽  
Neural Tube Closure ◽  
Cell Behavior ◽  
Apical Constriction ◽  
Cell Intercalation ◽  
Shape Changes

AbstractMorphogenesis of the neural tube in vertebrates relies on elongation and bending of the neural plate epithelium, which is driven at the cellular level by polarized cell intercalation, cell shape changes, and the underlying cytoskeletal dynamics that promotes these behaviors. Mutations of the gene encoding Scribble (Scrib) lead to neural tube defects in mice, however the cellular and molecular mechanisms by which Scribble regulates neural cell behavior remain unknown. Our analysis of neural development in Scribble mutants characterizes several defects in overall tissue shape changes. Live cell imaging of mouse embryos revealed that the Scrib mutation leads to defects in polarized cell intercalation and rosette resolution, as well as loss of apical constriction and cell wedging. Scrib mutant embryos displayed aberrant localization and expression of the junctional proteins ZO-1, Par3, Par6, aPKC, and cadherins, as well as the cytoskeletal proteins actin and myosin. These findings identify a novel role for Scrib in regulating neural cell behavior during NTC and further our understanding of the molecular mechanisms involved in mammalian neural development.

Expression of Bone Morphogenetic Proteins and Msx Genes during Root Formation

2003 ◽  
Vol 82 (3) ◽  
pp. 172-176 ◽  
Author(s):  
T. Yamashiro ◽  
M. Tummers ◽  
I. Thesleff
Keyword(s):  
Signaling Pathway ◽  
Bone Morphogenetic Proteins ◽  
Root Development ◽  
Root Formation ◽  
Expression Patterns ◽  
Bmp Signaling ◽  
Root Sheath ◽  
Crown Shape ◽  
Msx Genes ◽  
Tooth Germs

Like crown development, root formation is also regulated by interactions between epithelial and mesenchymml tissues. Bone morphogenetic proteins (BMPs), together with the transcription factors Msx1 and Msx2, play important roles in these interactions during early tooth morphogenesis. To investigate the involvement of this signaling pathway in root development, we analyzed the expression patterns of Bmp2, Bmp3, Bmp4, and Bmp7 as well as Msx1 and Msx2 in the roots of mouse molars. Bmp4 was expressed in the apical mesenchyme and Msx2 in the root sheath. However, Bmps were not detected in the root sheath epithelium, and Msx transcripts were absent from the underlying mesenchyme. These findings indicate that this Bmp signaling pathway, required for tooth initiation, does not regulate root development, but we suggest that root shape may be regulated by a mechanism similar to that regulating crown shape in cap-stage tooth germs. Msx2 expression continued in the epithelial cell rests of Malassez, and the nearby cementoblasts intensely expressed Bmp3, which may regulate some functions of the fragmented epithelium.

scholarly journals Bhlhe40/Sirt1 Axis-Regulated Mitophagy Is Implicated in All-Trans Retinoic Acid-Induced Spina Bifida Aperta

2021 ◽  
Vol 9 ◽  
Author(s):  
Lu Zhao ◽  
Dan Liu ◽  
Wei Ma ◽  
Hui Gu ◽  
Xiaowei Wei ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Spina Bifida ◽  
Neural Tube ◽  
Molecular Mechanisms ◽  
Underlying Mechanism ◽  
Neural Tube Closure ◽  
Luciferase Reporter ◽  
All Trans Retinoic Acid ◽  
Spina Bifida Aperta ◽  
First Time

Neural tube defects (NTDs) are the most severe congenital malformations that result from failure of neural tube closure during early embryonic development, and the underlying molecular mechanisms remain elusive. Mitophagy is the best-known way of mitochondrial quality control. However, the role and regulation of mitophagy in NTDs have not yet been elucidated. In this study, we used an all-trans retinoic acid (ATRA)-induced rat model to investigate mitophagy and its underlying mechanism in spina bifida aperta (SBA). The results of western blot, immunofluorescence and RT-qPCR analyses indicated that mitophagy was impaired and Sirt1 was downregulated in SBA. Administration of resveratrol-a strong specific Sirt1 activator-activated Sirt1, thus attenuating autophagy suppression and ameliorating SBA. RNA-sequencing and bioinformatics analysis results indicated that transcriptional regulation played an important role in NTDs. A luciferase reporter assay was performed to demonstrate that the transcription factor Bhlhe40 directly bound to and negatively regulated Sirt1 expression. Further, we discovered that the Bhlhe40/Sirt1 axis regulated mitophagy in neural stem cells. Collectively, our results for the first time demonstrate that Bhlhe40/Sirt1 axis regulated mitophagy is implicated in ATRA-induced SBA. Our findings provide new insights into pathogenesis of NTDs and a basis for potential therapeutic targets for NTDs.

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