Smad4 Regulates Ureteral Smooth Muscle Cell Differentiation during Mouse Embryogenesis

Yan, Jianyun; Zhang, Lu; Xu, Jinshu; Sultana, Nishat; Hu, Jun; Cai, Xiaoqiang; Li, Jun; Xu, Pin-Xian; Cai, Chen-Leng

doi:10.1371/journal.pone.0104503

Cited by 16 publications

(15 citation statements)

References 53 publications

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“…Some of these models do not develop smooth muscle throughout the whole ureter [9], while others lack smooth muscle only proximally [64]. These lead, in turn, to dilation of the whole ureter [9] or just the proximal ureter [64]. This dilation is thought to result from a lack of peristalsis in the absence of smooth muscle.…”

Section: (A) Urinary Systemmentioning

confidence: 99%

Smooth muscle: a stiff sculptor of epithelial shapes

Jaslove

Nelson

2018

Phil. Trans. R. Soc. B

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Smooth muscle is increasingly recognized as a key mechanical sculptor of epithelia during embryonic development. Smooth muscle is a mesenchymal tissue that surrounds the epithelia of organs including the gut, blood vessels, lungs, bladder, ureter, uterus, oviduct and epididymis. Smooth muscle is stiffer than its adjacent epithelium and often serves its morphogenetic function by physically constraining the growth of a proliferating epithelial layer. This constraint leads to mechanical instabilities and epithelial morphogenesis through buckling. Smooth muscle stiffness alone, without smooth muscle cell shortening, seems to be sufficient to drive epithelial morphogenesis. Fully understanding the development of organs that use smooth muscle stiffness as a driver of morphogenesis requires investigating how smooth muscle develops, a key aspect of which is distinguishing smooth musclelike tissues from one another in vivo and in culture. This necessitates a comprehensive appreciation of the genetic, anatomical and functional markers that are used to distinguish the different subtypes of smooth muscle (for example, vascular versus visceral) from similar cell types (including myofibroblasts and myoepithelial cells). Here, we review how smooth muscle acts as a mechanical driver of morphogenesis and discuss ways of identifying smooth muscle, which is critical for understanding these morphogenetic events.

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Section: (A) Urinary Systemmentioning

confidence: 99%

Smooth muscle: a stiff sculptor of epithelial shapes

Jaslove

Nelson

2018

Phil. Trans. R. Soc. B

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“…The defection in urothelial differentiation can cause UPJO in mice (13). Previous studies have found increased Shh and decreased Gli3 expression in children with UPJO (4).…”

Section: Discussionmentioning

confidence: 99%

The Expression of Ptch1 and Ptch2 in the Stenotic Tissue of Congenital Ureteropelvic Junction Obstruction in Children

YANG

han

Zhang

et al. 2020

Preprint

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Background: Ptch1 and Ptch2 are expressed in tubular epithelium and stromal cells adjacent to the UPJ. They mediate inhibition of Smoothened, a transmembrane protein expressed on the cell surface. If the pathway is disturbed, UPJOcan occur. This aim study aimed to determine the expression of Ptch1 (P1) and Ptch2 (P2) in stenotic segments in children with congenital ureteropelvic junction obstruction (UPJO) compared with normal control subjects. Methods: Stenotic segments of ureter tissues were obtained from 20 UPJO patients.UPJO caused by other pathogenies, such as vessel and ureteral polyps, were excluded. The control ureter specimens were obtained from 10 patients with Wilm’s tumor, and the tissues were confirmed histologically to be unaffected. Immunofluorescence, western blot and real-time PCR were used to investigate the expression of P1 and P2. Statistical methods were used to find the differences between the two groupsResults: P1 and P2 were identified in the cytoplasm of smooth muscle in two groups through immunohistochemistry. However, there were no statistical differences between the two groups in P1 and P2 with immunohistochemistry (P=0.31 and P=0.3, respectively). There were also no statistical differences with western blot (P=0.75 and P=0.9, respectively) and real-time PCR (P=0.52 and P=0.45, respectively). However, with the immunofluorescence it was found that red-stained P1 were diffused in the controls group, but were mainly located in the intracellular perinuclear compartment of smooth muscle cells in UPJO. Conclusions: The expression of P1 and P2 between the two groups had no statistical significant. P1 were mainly located in the intracellular perinuclear compartment of smooth muscle cells in UPJO. The P1 pathway might be disturbed by the abnormal distribution rather than the quantity, which might be one probable pathogenesis of UPJO.

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“…To investigate the role of Smad4 in limb formation, we utilized new Tbx18 Cre/ϩ knock-in mice (24), with which to remove Smad4 in the proximal domain of forelimbs and hindlimbs in mouse embryos (Fig. S1, A and B).…”

Section: Deletion Of Smad4 Disrupts Skeletal Developmentmentioning

confidence: 99%

Smad4 deficiency impairs chondrocyte hypertrophy via the Runx2 transcription factor in mouse skeletal development

Yan

et al. 2018

Journal of Biological Chemistry

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Chondrocyte hypertrophy is the terminal step in chondrocyte differentiation and is crucial for endochondral bone formation. How signaling pathways regulate chondrocyte hypertrophic differentiation remains incompletely understood. In this study, using a () gene-deletion approach, we selectively deleted the gene for the signaling protein SMAD family member 4 ( ) in the limbs of mice. We found that the -deficient mice develop a prominent shortened limb, with decreased expression of chondrocyte differentiation markers, including and , in the humerus at mid-to-late gestation. The most striking defects in these mice were the absence of stylopod elements and failure of chondrocyte hypertrophy in the humerus. Moreover, expression levels of the chondrocyte hypertrophy-related markers and were significantly decreased. Of note, we also observed that the expression of runt-related transcription factor 2 (), a critical mediator of chondrocyte hypertrophy, was also down-regulated in -deficient limbs. To determine how the skeletal defects arose in the mouse mutants, we performed RNA-Seq with ChIP-Seq analyses and found that Smad4 directly binds to regulatory elements in the promoter. Our results suggest a new mechanism whereby Smad4 controls chondrocyte hypertrophy by up-regulating expression during skeletal development. The regulatory mechanism involving Smad4-mediated activation uncovered here provides critical insights into bone development and pathogenesis of chondrodysplasia.

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Smad4 Regulates Ureteral Smooth Muscle Cell Differentiation during Mouse Embryogenesis

Cited by 16 publications

References 53 publications

Smooth muscle: a stiff sculptor of epithelial shapes

Smooth muscle: a stiff sculptor of epithelial shapes

The Expression of Ptch1 and Ptch2 in the Stenotic Tissue of Congenital Ureteropelvic Junction Obstruction in Children

Smad4 deficiency impairs chondrocyte hypertrophy via the Runx2 transcription factor in mouse skeletal development

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