Mammalian twisted gastrulation is essential for skeleto-lymphogenesis.
Dorsoventral patterning depends on the local concentrations of the morphogens. Twisted gastrulation (TSG) regulates the extracellular availability of a mesoderm inducer, bone morphogenetic protein 4 (BMP-4). However, TSG function in vivo is still unclear. We isolated a TSG cDNA as a secreted molecule from the mouse aorta-gonad-mesonephros region. Here we show that TSG-deficient mice were born healthy, but more than half of the neonatal pups showed severe growth retardation shortly after birth and displayed dwarfism with delayed endochondral ossification and lymphopenia, followed by death within a month. TSG-deficient thymus was atrophic, and phosphorylation of SMAD1 was augmented in the thymocytes, suggesting enhanced BMP-4 signaling in the thymus. Since BMP-4 promotes skeletogenesis and inhibits thymus development, our findings suggest that TSG acts as both a BMP-4 agonist in skeletogenesis and a BMP-4 antagonist in T-cell development. Although lymphopenia in TSG-deficient mice would partly be ascribed to systemic effects of runtiness and wasting, our findings may also provide a clue for understanding the pathogenesis of human dwarfism with combined immunodeficiency.
Nosaka
Tetsuya
T
Division of Hematopoietic Factors, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. tenosaka@ims.u-tokyo.ac.jp
Morita
Sumiyo
S
Kitamura
Hidetomo
H
Nakajima
Hideaki
H
Shibata
Fumi
F
Morikawa
Yoshihiro
Y
Kataoka
Yuki
Y
Ebihara
Yasuhiro
Y
Kawashima
Toshiyuki
T
Itoh
Tsuneo
T
Ozaki
Katsutoshi
K
Senba
Emiko
E
Tsuji
Kohichiro
K
Makishima
Fusao
F
Yoshida
Nobuaki
N
Kitamura
Toshio
T
D000818:Animals; D001846:Bone Development / Q000235:genetics* / Q000502:physiology; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors*; D002454:Cell Differentiation; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005314:Embryonic and Fetal Development / Q000235:genetics; D018390:Gene Targeting; D006130:Growth Disorders / Q000235:genetics / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D007668:Kidney / Q000002:abnormalities; D008221:Lymphoid Tissue / Q000196:embryology* / Q000254:growth & development; D008231:Lymphopenia / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D051785:Smad Proteins; D051898:Smad1 Protein; D013601:T-Lymphocytes / Q000166:cytology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics
C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; C497399:SMAD1 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C473561:twisted gastrulation protein, mouse