Genetic interactions between activin type IIB receptor and Smad2 genes in asymmetrical patterning of the thoracic organs and the development of pancreas islets.
Signaling through activin type IIB receptor (ActRIIB) has been shown to regulate the axial formation and the development of foregut-derived organs such as the pancreas in mice. Here, we provide genetic evidence that ActRIIB and Smad2 genes cooperatively regulated asymmetrical patterning of the thoracic organs and pancreas development in mice. The loss of one allele of Smad2 on ActRIIB-/- background resulted in the increased severity of ActRIIB-/- phenotypes, including right pulmonary isomerism and complex cardiac malformations, and resulted in 100% frequency of death soon after birth. Of interest, 14% of compound heterozygous ActRIIB+/- Smad2+/- mice exhibited the ActRIIB-/- phenotypes and died soon after birth. In the pancreas, hypoplastic islets were found not only in ActRIIB-/- but also in Smad2+/- mice. A more severe phenotype was also found in ActRIIB+/- Smad2+/- mice. As well, these mutant mice exhibited impaired glucose tolerance in a gene dosage-sensitive manner. This genetic evidence strongly suggested that ActRIIB and Smad2 function in the same signaling pathway to regulate axial patterning and pancreas islet formation by means of a threshold mechanism.
Goto
Yutaka
Y
Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.
Nomura
Masatoshi
M
Tanaka
Kimitaka
K
Kondo
Akiyo
A
Morinaga
Hidetaka
H
Okabe
Taijirou
T
Yanase
Toshihiko
T
Nawata
Hajime
H
Takayanagi
Ryoichi
R
Li
En
E
D030301:Activin Receptors, Type II / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D019521:Body Patterning; D047108:Embryonic Development; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000002:abnormalities / Q000196:embryology*; D008168:Lung / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010179:Pancreas / Q000002:abnormalities / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics* / Q000378:metabolism
D007328:Insulin; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B