The phosphatase Dullard negatively regulates BMP signalling and is essential for nephron maintenance after birth.
Most kidney nephron components, including glomeruli and renal tubules, derive from the metanephric mesenchyme. The overall differentiation into each component finishes at birth, but the molecular events linking the perinatal and adult kidneys remain elusive. Dullard was cloned from Xenopus kidneys, and encodes a phosphatase that negatively regulates BMP signalling. Here we report that Dullard deletion in the murine metanephric mesenchyme leads to failure of nephron maintenance after birth, resulting in lethality before adulthood. The nephron components are lost by massive apoptosis within 3 weeks after birth, leading to formation of a large hollow with a thin-layered cortex and medulla. Phosphorylated Smad1/5/8 is upregulated in the mutant nephrons, probably through cell-autonomous inhibitory effects of Dullard on BMP signalling. Importantly, administration of the BMP receptor kinase inhibitor LDN-193189 partially rescued the defects caused by Dullard deletion. Thus, Dullard keeps BMP signalling at an appropriate level, which is required for nephron maintenance in the postnatal period.
Department of Kidney Development, Institute of Molecular Embryology and Genetics, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
Masaji
M
Sakaguchi
Sazia
S
Sharmin
Atsuhiro
A
Taguchi
Tomoko
T
Ohmori
Sayoko
S
Fujimura
Takaya
T
Abe
Hiroshi
H
Kiyonari
Yoshihiro
Y
Komatsu
Yuji
Y
Mishina
Makoto
M
Asashima
Eiichi
E
Araki
Ryuichi
R
Nishinakamura
D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D015153:Blotting, Western; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002460:Cell Line; D051379:Mice; D008817:Mice, Mutant Strains; D009399:Nephrons / Q000196:embryology / Q000201:enzymology* / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction; D013194:Staining and Labeling
D019485:Bone Morphogenetic Proteins; C581756:Dullard protein, mouse; D010749:Phosphoprotein Phosphatases