title: 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 (α-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.
authors.affiliation: Department of Developmental and Regenerative Biology, The Mindich Child Health and Development Institute, and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Histology and Embryology, Southern Medical University, Guangzhou, China.
authors.forename: Jianyun
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Developmental and Regenerative Biology, The Mindich Child Health and Development Institute, and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Developmental and Regenerative Biology, The Mindich Child Health and Development Institute, and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Jinshu
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Developmental and Regenerative Biology, The Mindich Child Health and Development Institute, and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Nishat
authors.initials: N
authors.lastname: Sultana
authors.affiliation: Department of Developmental and Regenerative Biology, The Mindich Child Health and Development Institute, and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Developmental and Regenerative Biology, The Mindich Child Health and Development Institute, and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Developmental and Regenerative Biology, The Mindich Child Health and Development Institute, and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Developmental and Regenerative Biology, The Mindich Child Health and Development Institute, and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Pin-Xian
authors.initials: PX
authors.lastname: Xu
authors.affiliation: Department of Developmental and Regenerative Biology, The Mindich Child Health and Development Institute, and The Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Chen-Leng
authors.initials: CL
authors.lastname: Cai
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics; D055879:Gene Knock-In Techniques; D006869:Hydronephrosis / Q000235:genetics; D017403:In Situ Hybridization; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis; D038081:Organogenesis / Q000235:genetics*; D055758:SOX9 Transcription Factor / Q000096:biosynthesis; D051901:Smad4 Protein / Q000235:genetics*; D024745:Smooth Muscle Myosins / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D015534:Trans-Activators / Q000096:biosynthesis; D014513:Ureter / Q000166:cytology* / Q000502:physiology; D000099251:Myocardin
chemical_list: D000199:Actins; D018995:Myosin Heavy Chains; D009687:Nuclear Proteins; D055758:SOX9 Transcription Factor; D051901:Smad4 Protein; D024745:Smooth Muscle Myosins; D020825:T-Box Domain Proteins; D015534:Trans-Activators; D000099251:Myocardin; C490810:Smad4 protein, mouse; C527933:Sox9 protein, mouse; C420983:Tbx18 protein, mouse; C544013:alpha-smooth muscle actin, mouse