title: Cell autonomous roles of Nedd4 in craniofacial bone formation.
abstract: Nedd4 is an E3 ubiquitin ligase that has an essential role in craniofacial development. However, how and when Nedd4 controls skull formation is ill defined. Here we have used a collection of complementary genetic mouse models to dissect the cell-autonomous roles of Nedd4 in the formation of neural crest cell derived cranial bone. Removal of Nedd4 specifically from neural crest cells leads to profound craniofacial defects with marked reduction of cranial bone that was preceded by hypoplasia of bone forming osteoblasts. Removal of Nedd4 after differentiation of neural crest cells into progenitors of chondrocytes and osteoblasts also led to profound deficiency of craniofacial bone in the absence of cartilage defects. Notably, these skull malformations were conserved when Nedd4 was specifically removed from the osteoblast lineage after specification of osteoblast precursors from mesenchymal skeletal progenitors. We further show that absence of Nedd4 in pre-osteoblasts results in decreased cell proliferation and altered osteogenic differentiation. Taken together our data demonstrate a novel cell-autonomous role for Nedd4 in promoting expansion of the osteoblast progenitor pool to control craniofacial development. Nedd4 mutant mice therefore represent a unique mouse model of craniofacial anomalies that provide an ideal resource to explore the cell-intrinsic mechanisms of neural crest cells in craniofacial morphogenesis.
authors.affiliation: Centre for Cancer Biology and University of South Australia, Frome Road, Adelaide, SA 5000, Australia.
authors.forename: Sophie
authors.initials: S
authors.lastname: Wiszniak
authors.affiliation: Centre for Cancer Biology and University of South Australia, Frome Road, Adelaide, SA 5000, Australia.
authors.forename: Natasha
authors.initials: N
authors.lastname: Harvey
authors.affiliation: Centre for Cancer Biology and University of South Australia, Frome Road, Adelaide, SA 5000, Australia. Electronic address: quenten.schwarz@health.sa.gov.au.
authors.forename: Quenten
authors.initials: Q
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D019070:Cell Lineage; D049109:Cell Proliferation; D056827:Endosomal Sorting Complexes Required for Transport / Q000502:physiology*; D005147:Facial Bones / Q000196:embryology*; D051379:Mice; D000075702:Nedd4 Ubiquitin Protein Ligases; D009432:Neural Crest / Q000502:physiology; D010006:Osteoblasts / Q000166:cytology; D010012:Osteogenesis; D012886:Skull / Q000196:embryology*; D051898:Smad1 Protein / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Craniofacial development; Nedd4; Neural crest cell; Ossification; Osteoblast