Cv2, functioning as a pro-BMP factor via twisted gastrulation, is required for early development of nephron precursors.
The fine-tuning of BMP signals is critical for many aspects of complex organogenesis. In this report, we show that the augmentation of BMP signaling by a BMP-binding secreted factor, Crossveinless2 (Cv2), is essential for the early embryonic development of mammalian nephrons. In the Cv2-null mouse, the number of cap condensates (clusters of nephron progenitors, which normally express Cv2) was decreased, and the condensate cells exhibited a reduced level of aggregation. In these Cv2(-/-) condensates, the level of phosphorylated Smad1 (pSmad1) was substantially lowered. The loss of a Bmp7 allele in the Cv2(-/-) mouse enhanced the cap condensate defects and further decreased the level of pSmad1 in this tissue. These observations indicated that Cv2 has a pro-BMP function in early nephrogenesis. Interestingly, the renal defects of the Cv2(-/-) mutant were totally suppressed by a null mutation of Twisted gastrulation (Tsg), which encodes another BMP-binding factor, showing that Cv2 exerts its pro-BMP nephrogenic function Tsg-dependently. By using an embryonic kidney cell line, we presented experimental evidence showing that Cv2 enhances pro-BMP activity of Tsg. These findings revealed the molecular hierarchy between extracellular modifiers that orchestrate local BMP signal peaks in the organogenetic microenvironment.
Ikeya
Makoto
M
Organogenesis and Neurogenesis Group, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo, Kobe 650-0047, Japan. mikeya@cdb.riken.jp
Fukushima
Kumi
K
Kawada
Masako
M
Onishi
Sachiko
S
Furuta
Yasuhide
Y
Yonemura
Shigenobu
S
Kitamura
Toshio
T
Nosaka
Tetsuya
T
Sasai
Yoshiki
Y
D000818:Animals; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002449:Cell Aggregation; D002478:Cells, Cultured; D004843:Epistasis, Genetic; D007685:Kidney Tubules, Collecting / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009399:Nephrons / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D011506:Proteins / Q000378:metabolism*; D015398:Signal Transduction
D055419:Bone Morphogenetic Protein 7; D002352:Carrier Proteins; D011506:Proteins; C517553:crossveinless 2 protein, mouse; C473561:twisted gastrulation protein, mouse