The ubiquitin ligase Nedd4 regulates craniofacial development by promoting cranial neural crest cell survival and stem-cell like properties.
The integration of multiple morphogenic signalling pathways and transcription factor networks is essential to mediate neural crest (NC) cell induction, delamination, survival, stem-cell properties, fate choice and differentiation. Although the transcriptional control of NC development is well documented in mammals, the role of post-transcriptional modifications, and in particular ubiquitination, has not been explored. Here we report an essential role for the ubiquitin ligase Nedd4 in cranial NC cell development. Our analysis of Nedd4(-/-) embryos identified profound deficiency of cranial NC cells in the absence of structural defects in the neural tube. Nedd4 is expressed in migrating cranial NC cells and was found to positively regulate expression of the NC transcription factors Sox9, Sox10 and FoxD3. We found that in the absence of these factors, a subset of cranial NC cells undergo apoptosis. In accordance with a lack of cranial NC cells, Nedd4(-/-) embryos have deficiency of the trigeminal ganglia, NC derived bone and malformation of the craniofacial skeleton. Our analyses therefore uncover an essential role for Nedd4 in a subset of cranial NC cells and highlight E3 ubiquitin ligases as a likely point of convergence for multiple NC signalling pathways and transcription factor networks.
Centre for Cancer Biology, SA Pathology, Frome Road, Adelaide, 5000, Australia.
Sophie
S
Wiszniak
Samuela
S
Kabbara
Rachael
R
Lumb
Michaela
M
Scherer
Genevieve
G
Secker
Natasha
N
Harvey
Sharad
S
Kumar
Quenten
Q
Schwarz
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D019521:Body Patterning; D001921:Brain / Q000166:cytology* / Q000196:embryology*; D049109:Cell Proliferation; D002470:Cell Survival; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005145:Face / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D009432:Neural Crest / Q000166:cytology*; D010641:Phenotype; D012249:Rhombencephalon / Q000166:cytology / Q000196:embryology; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000166:cytology / Q000196:embryology; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; D056827:Endosomal Sorting Complexes Required for Transport; D014157:Transcription Factors; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases
Ectomesenchyme; Nedd4; Neural crest cell; Neuroglial; Stem-cell maintenance; Ubiquitin ligase