Bhlha9 regulates apical ectodermal ridge formation during limb development.
Split hand/foot malformation (SHFM) and SHFM combined with long-bone deficiency (SHFLD) are congenital dysgeneses of the limb. Although six different loci/mutations (SHFM1-SHFM6) have been found from studies on families with SHFM, the causes and associated pathogenic mechanisms for a large number of patients remain unidentified. On the basis of the identification of a duplicated gene region involving BHLHA9 in some affected families, BHLHA9 was identified as a novel SHFM/SHFLD-related gene. Although Bhlha9 is predicted to participate in limb development as a transcription factor, its precise function is unclear. Therefore, to study its physiological function, we generated a Bhlha9-knockout mouse and investigated gene expression and the associated phenotype in the limb bud. Bhlha9-knockout mice showed syndactyly and poliosis in the limb. Moreover, some apical ectodermal ridge (AER) formation related genes, including Trp63, exhibited an aberrant expression pattern in the limb bud of Bhlha9-knockout mice; TP63 (Trp63) was regulated by Bhlha9 on the basis of in vitro analysis. These observations suggest that Bhlha9 regulates AER formation during limb/finger development by regulating the expression of some AER-formation-related genes and abnormal expression of Bhlha9 leads to SHFM and SHFLD via dysregulation of AER formation and associated gene expression.
Department of Systems BioMedicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Kensuke
K
Kataoka
Department of Systems BioMedicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Takahide
T
Matsushima
Department of Systems BioMedicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Yoshiaki
Y
Ito
Department of Systems BioMedicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
Tempei
T
Sato
Department of Systems Biomedicine, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-0074, Japan.
Shigetoshi
S
Yokoyama
Department of Systems BioMedicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan. asahara.syst@tmd.ac.jp.|Department of Systems Biomedicine, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo, 157-0074, Japan. asahara.syst@tmd.ac.jp.
Hiroshi
H
Asahara
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D004475:Ectoderm / Q000196:embryology* / Q000378:metabolism*; D005121:Extremities / Q000196:embryology*; D051524:Fibroblast Growth Factor 8 / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006367:HeLa Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
D051792:Basic Helix-Loop-Helix Proteins; D051524:Fibroblast Growth Factor 8; D010750:Phosphoproteins; D015534:Trans-Activators; C571985:BHLHA9 protein, human; C496457:Fgf8 protein, mouse; C486419:Trp63 protein, mouse; C000598252:bHLHA9 protein, mouse
Bhlha9; Split hand/foot malformation; Split hand/foot malformation combined with long-bone deficiency