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Smad4 regulates ureteral smooth muscle cell differentiation during mouse embryogenesis.

ABSTRACT: Proper formation of ureteral smooth muscle cells (SMCs) during embryogenesis is essential for ureter peristalsis that propels urine from the kidney to the bladder in mammals. Currently the molecular factors that regulate differentiation of ureteral mesenchymal cells into SMCs are incompletely understood. A recent study has reported that Smad4 deficiency reduces the number of ureteral SMCs. However, its precise role in the ureteral smooth muscle development remains largely unknown. Here, we used Tbx18:Cre knock-in mouse line to delete Smad4 to examine its requirement in the development of ureteral mesenchyme and SMC differentiation. We found that mice with specific deletion of Smad4 in Tbx18-expressing ureteral mesenchyme exhibited hydroureter and hydronephrosis at embryonic day (E) 16.5, and the mutant mesenchymal cells failed to differentiate into SMCs with increased apoptosis and decreased proliferation. Molecular markers for SMCs including alpha smooth muscle actin (?-SMA) and smooth muscle myosin heavy chain (SM-MHC) were absent in the mutant ureters. Moreover, disruption of Smad4 significantly reduced the expression of genes, including Sox9, Tbx18 and Myocardin associated with SMC differentiation. These findings suggest that Smad4 is essential for initiating the SMC differentiation program during ureter development.

SUBMITTER: Yan J

PROVIDER: S-EPMC4134214 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Smad4 regulates ureteral smooth muscle cell differentiation during mouse embryogenesis.

Yan Jianyun J Zhang Lu L Xu Jinshu J Sultana Nishat N Hu Jun J Cai Xiaoqiang X Li Jun J Xu Pin-Xian PX Cai Chen-Leng CL

PloS one 20140815 8

Proper formation of ureteral smooth muscle cells (SMCs) during embryogenesis is essential for ureter peristalsis that propels urine from the kidney to the bladder in mammals. Currently the molecular factors that regulate differentiation of ureteral mesenchymal cells into SMCs are incompletely understood. A recent study has reported that Smad4 deficiency reduces the number of ureteral SMCs. However, its precise role in the ureteral smooth muscle development remains largely unknown. Here, we used ...[more]

PMID: 25127126

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Project description:Smad4 is a central mediator of transforming growth factor-?/bone morphogenetic protein signaling that controls numerous developmental processes as well as homeostasis in the adult. The present studies sought to understand the function of Smad4 expressed in vascular smooth muscle cells (VSMC) in vascular development and the underlying mechanisms.Breeding of Smad4(flox/flox) mice with SM22?-Cre mice resulted in no viable offspring with SM22?-Cre;Smad4(flox/flox) genotype in a total of 165 newborns. Subsequent characterization of 301 embryos between embryonic day (E) 9.5 and E14.5 demonstrated that mice with SM22?-Cre;Smad4(flox/flox) genotype died between E12.5 and E14.5 because of decreased cell proliferation and increased apoptosis in the embryonic heart and arteries. Additionally, deletion of Smad4 more specifically in SMC with the inducible smooth muscle myosin heavy chain (SMMHC)-Cre mice, in which decreased cell proliferation was observed only in the artery but not the heart, also caused lethality of the knockout embryos at E12.5 and E14.5. The Smad4-deficient VSMC lacked smooth muscle ?-actin filaments, decreased expression of SMC-specific gene markers, and markedly reduced cell proliferation, migration, and attachment. Using specific pharmacological inhibitors and small interfering RNAs, we demonstrated that inhibition of transforming growth factor-? signaling and its regulatory Smad 2/3 decreased VSMC proliferation, migration, and expression of SMC-specific gene markers, whereas inhibition of bone morphogenetic protein signaling only affected VSMC migration.SMC-specific deletion of Smad4 results in vascular defects that lead to embryonic lethality in mice, which may be attributed to decreased VSMC differentiation, proliferation, migration, as well as cell attachment and spreading. The transforming growth factor-? signaling pathway contributes to VSMC differentiation and function, whereas the bone morphogenetic protein signaling pathway regulates VSMC migration. These studies provide important insight into the role of Smad4 and its upstream Smads in regulating SMC function and vascular development of mice.

Dataset Information

Smad4 regulates ureteral smooth muscle cell differentiation during mouse embryogenesis.

Publications

Smad4 regulates ureteral smooth muscle cell differentiation during mouse embryogenesis.

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