Tbx22null mice have a submucous cleft palate due to reduced palatal bone formation and also display ankyloglossia and choanal atresia phenotypes.
Craniofacial defects involving the lip and/or palate are among the most common human birth defects. X-linked cleft palate and ankyloglossia results from loss-of-function mutations in the gene encoding the T-box transcription factor TBX22. Further studies show that TBX22 mutations are also found in around 5% of non-syndromic cleft palate patients. Although palate defects are obvious at birth, the underlying developmental pathogenesis remains unclear. Here, we report a Tbx22(null) mouse, which has a submucous cleft palate (SMCP) and ankyloglossia, similar to the human phenotype, with a small minority showing overt clefts. We also find persistent oro-nasal membranes or, in some mice a partial rupture, resulting in choanal atresia. Each of these defects can cause severe breathing and/or feeding difficulties in the newborn pups, which results in approximately 50% post-natal lethality. Analysis of the craniofacial skeleton demonstrates a marked reduction in bone formation in the posterior hard palate, resulting in the classic notch associated with SMCP. Our results suggest that Tbx22 plays an important role in the osteogenic patterning of the posterior hard palate. Ossification is severely reduced after condensation of the palatal mesenchyme, resulting from a delay in the maturation of osteoblasts. Rather than having a major role in palatal shelf closure, we show that Tbx22 is an important determinant for intramembranous bone formation in the posterior hard palate, which underpins normal palate development and function. These findings could have important implications for the molecular diagnosis in patients with isolated SMCP and/or unexplained choanal atresia.
Pauws
Erwin
E
UCL Institute of Child Health, 30 Guilford Street, WC1N 1EH London, UK.
Hoshino
Aya
A
Bentley
Lucy
L
Prajapati
Suresh
S
Keller
Charles
C
Hammond
Peter
P
Martinez-Barbera
Juan-Pedro
JP
Moore
Gudrun E
GE
Stanier
Philip
P
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002754:Choanal Atresia / Q000473:pathology*; D002972:Cleft Palate / Q000473:pathology*; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017403:In Situ Hybridization; D008035:Lingual Frenum / Q000002:abnormalities*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010159:Palate / Q000002:abnormalities; D010641:Phenotype; D020825:T-Box Domain Proteins / Q000235:genetics*
D020825:T-Box Domain Proteins; C534956:Tbx22 protein, mouse