Signaling through Tgf-beta type I receptor Alk5 is required for upper lip fusion.
Cleft lip with or without cleft palate is one of the most common congenital malformations in newborns. While numerous studies on secondary palatogenesis exist, data regarding normal upper lip formation and cleft lip is limited. We previously showed that conditional inactivation of Tgf-beta type I receptor Alk5 in the ectomesenchyme resulted in total facial clefting. While the role of Tgf-beta signaling in palatal fusion is relatively well understood, its role in upper lip fusion remains unknown. In order to investigate a role for Tgf-beta signaling in upper lip formation, we used the Nes-Cre transgenic mouse line to delete the Alk5 gene in developing facial prominences. We show that Alk5/Nes-Cre mutants display incompletely penetrant unilateral or bilateral cleft lip. Increased cell death seen in the medial nasal process and the maxillary process may explain the hypoplastic maxillary process observed in mutants. The resultant reduced contact is insufficient for normal lip fusion leading to cleft lip. These mice also display retarded development of palatal shelves and die at E15. Our findings support a role for Alk5 in normal upper lip formation not previously reported.
Li
Wai-Yee
WY
Developmental Biology Program, The Saban Research Institute of Childrens Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027, USA.
Dudas
Marek
M
Kaartinen
Vesa
V
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D002971:Cleft Lip / Q000378:metabolism / Q000473:pathology; D004475:Ectoderm / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D005145:Face / Q000196:embryology; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D019426:Integrases / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008046:Lip / Q000196:embryology* / Q000378:metabolism*; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009297:Nasal Mucosa / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D009666:Nose / Q000196:embryology; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D011995:Recombination, Genetic / Q000235:genetics; D015398:Signal Transduction
D055415:Bone Morphogenetic Protein 4; D053823:Hedgehog Proteins; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D018125:Receptors, Transforming Growth Factor beta; C465570:Shh protein, mouse; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse; C045073:Cre recombinase; D019426:Integrases