Genetic analysis of the role of Alx4 in the coordination of lower body and external genitalia formation.
Although several syndromes include abnormalities of both the ventral body wall and external genitalia, the developmental bases of this correlation are largely unknown. Naturally occurring mutations in Aristaless-like 4 (Alx4, Strong's luxoid: Alx4Lst) have ventral body wall and pelvic girdle abnormalities. We sought to determine whether the development of the genital tubercle (GT) and its derivatives, the external genitalia, is affected by this mutation. We thus performed genetic and tissue labeling analyses in mutant mice. Alx4Lst/Lst mutants displayed hypoplasia of the dorsal GT and reduced expression of Fibronectin. We analyzed cell migration during GT formation by tissue labeling experiments and discovered that the cells located in the proximal segment of the umbilical cord (infra-umbilical mesenchyme) migrate toward the dorsal part of the GT. The Alx4Lst/Lst mutants also displayed augmented expression of Hh signal-related genes. Hence, we analyzed a series of combinatorial mutants for Alx4, Sonic hedgehog (Shh) and GLI-Kruppel family member 3 (Gli3). These phenotype-genotype analyses suggested a genetic interaction between Alx4 and Hh signaling during GT formation. Moreover, Hh gain-of-function mutants phenocopied some of these phenotypes. These observations reveal novel information regarding the pathogenic mechanisms of syndromic lower ventral body malformations, which are largely unknown.
1] Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan [2] Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
Daisuke
D
Matsumaru
1] Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan [2] Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan [3] Department of Molecular Pathology, Ehime University Graduate School of Medicine, Ehime, Japan.
Ryuma
R
Haraguchi
Weis Center for Research, Geisinger Clinic, Danville, PA, USA.
Anne M
AM
Moon
1] Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan [2] Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
Yoshihiko
Y
Satoh
Division of Reproductive Engineering, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan.
Naomi
N
Nakagata
Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
Ken-ichi
K
Yamamura
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
Naoki
N
Takahashi
Department of Molecular Pathology, Ehime University Graduate School of Medicine, Ehime, Japan.
Sohei
S
Kitazawa
1] Department of Developmental Genetics, Institute of Advanced Medicine, Wakayama Medical University, Wakayama, Japan [2] Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
Gen
G
Yamada
D000818:Animals; D002465:Cell Movement; D005260:Female; D005835:Genitalia / Q000002:abnormalities* / Q000196:embryology; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010388:Pelvis / Q000002:abnormalities* / Q000196:embryology; D014470:Umbilical Cord / Q000196:embryology / Q000473:pathology; D000074290:Zinc Finger Protein Gli3
C109218:Alx4 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C465570:Shh protein, mouse; D000074290:Zinc Finger Protein Gli3