GLI3 repressor controls functional development of the mouse ureter

Cain, Jason; Islam, Epshita A.; Haxho, Fiona; Blake, Joshua; Rosenblum, Norman D.

doi:10.1172/jci45523

Cited by 75 publications

(98 citation statements)

References 42 publications

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“…In mice, loss of GLI2 does not result in a renal phenotype, but increased expression of GLI3R in a mouse model of Pallister-Hall syndrome causes nonobstructive hydronephrosis. 12 These findings suggest redundancy among the GLI activators in the kidney and highlight the essential function of GLI3R in maintaining appropriate Hh activity levels. Because GLI2 normally does not show a functional role in kidney development, attenuation of Thm1 renal cystogenesis by loss of GLI2 suggests that the Thm1 ciliary defect enhances GLI2 function in the postnatal kidney.…”

Section: Small Molecule Hh Inhibitors Do Notmentioning

confidence: 81%

“…In most tissues, GLI2 acts as the primary transcriptional activator (reviewed by Eggenschwiler and Anderson 10 ), although in certain tissues, GLI3 activator (GLI3A) or GLI3 repressor (GLI3R), which is formed by cleavage of the full-length GLI3 protein, plays a predominant role because of redundancy and/or tissue specificity of the GLI proteins. 11,12 Nonetheless, the balance between activity of GLI activators and GLI3 repressor determines level of Hh signaling output within a cell. 10,13 Despite the connection between primary cilia and Hh signaling, a role for Hh signaling in cystic kidney disease has not been studied extensively.…”

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confidence: 99%

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Downregulating Hedgehog Signaling Reduces Renal Cystogenic Potential of Mouse Models

Tran

Talbott

Turbé-Doan

et al. 2014

Journal of the American Society of Nephrology

110

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Renal cystic diseases are a leading cause of renal failure. Mutations associated with renal cystic diseases reside in genes encoding proteins that localize to primary cilia. These cystoproteins can disrupt ciliary structure or cilia-mediated signaling, although molecular mechanisms connecting cilia function to renal cystogenesis remain unclear. The ciliary gene, Thm1(Ttc21b), negatively regulates Hedgehog signaling and is most commonly mutated in ciliopathies. We report that loss of murine Thm1 causes cystic kidney disease, with persistent proliferation of renal cells, elevated cAMP levels, and enhanced expression of Hedgehog signaling genes. Notably, the cAMP-mediated cystogenic potential of Thm1-null kidney explants was reduced by genetically deleting Gli2, a major transcriptional activator of the Hedgehog pathway, or by culturing with small molecule Hedgehog inhibitors. These Hedgehog inhibitors acted independently of protein kinase A and Wnt inhibitors. Furthermore, simultaneous deletion of Gli2 attenuated the renal cystic disease associated with deletion of Thm1. Finally, transcripts of Hedgehog target genes increased in cystic kidneys of two other orthologous mouse mutants, jck and Pkd1, and Hedgehog inhibitors reduced cystogenesis in jck and Pkd1 cultured kidneys. Thus, enhanced Hedgehog activity may have a general role in renal cystogenesis and thereby present a novel therapeutic target.

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Section: Small Molecule Hh Inhibitors Do Notmentioning

confidence: 81%

mentioning

confidence: 99%

Downregulating Hedgehog Signaling Reduces Renal Cystogenic Potential of Mouse Models

Tran

Talbott

Turbé-Doan

et al. 2014

Journal of the American Society of Nephrology

110

View full text Add to dashboard Cite

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“…Therefore, the balance between the activities of Gli2/3 transcriptional activator and repressor dictates Hh responses that are both tissue-specific and developmental stage-specific. During limb and ureter development, Shh acts mainly by opposing Gli3 repression (16,17). During neural tube and skeletal development, integrated regulation of Gli2 activation and Gli3 de-repression has both overlapping and distinct functions (18 -21).…”

mentioning

confidence: 99%

Specific Requirement of Gli Transcription Factors in Hedgehog-mediated Intestinal Development

Huang

Cotton²,

Wang³

et al. 2013

Journal of Biological Chemistry

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Hedgehog (Hh) signaling is involved in multiple aspects of embryonic gut development, including mesenchymal growth and smooth muscle differentiation. The Gli family transcription factors is thought to collectively mediate Hh signaling in mammals. However, the function of different Gli proteins in gut development remains uncharacterized. Here, we genetically dissect the contribution of Gli transcriptional activation and de-repression in intestinal growth and patterning. We find that removal of the Gli3 repressor is dispensable for intestinal development and does not play a major role in Hh-controlled gut development. However, Gli2 activation is able to fully rescue the Smoothened (Smo)-null intestinal phenotype, suggesting that the Gli2 transcription factor is the main effector for Hh signaling in the intestine. To understand further the molecular mechanism underlying Hh/Gli function in the developing gut, we identify a subset of small leucine-rich glycoproteins (SLRPs) that may function downstream of Hh signaling in the mesenchyme. We show that osteoglycin, a SLRP, inhibits Hh-induced differentiation toward the smooth muscle lineage in C3H10T1/2 pluripotent mesenchymal cells. Taken together, our study reveals, for the first time, the distinct roles of Gli proteins in intestine development and suggests SLRPs as novel regulators of smooth muscle cell differentiation

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“…Targeted deletion of calcineurin b1 (Cnb1) or hedgehog effector smoothened (Smo) in periureteral mesenchyme in mice causes nonobstructive hydronephrosis, hydroureter and medullary hypoplasia not associated with abnormal collecting duct morphogenesis. 76,77 Thus, medullary hypoplasia observed in these mice may result from backward pressure to the renal parenchyma due to urinary stasis. The mechanisms that have been implicated in functional ureteral obstruction in these mice include defective ureteral peristalsis (failure of ureteral peristalsis to propagate in a sequential proximal-distal direction), reduced number of ureteral pacemaker cells and decreased proliferation of periureteral mesenchymal cells.…”

Section: Do Not Distributementioning

confidence: 99%

“…The mechanisms that have been implicated in functional ureteral obstruction in these mice include defective ureteral peristalsis (failure of ureteral peristalsis to propagate in a sequential proximal-distal direction), reduced number of ureteral pacemaker cells and decreased proliferation of periureteral mesenchymal cells. 76,77 Although medullary hypoplasia and hydronephrosis observed in angiotensin (Ang) II AT1 receptor (AT1R)-deficient mice may result from impaired ureteral peristalsis due to hypoplastic ureteral smooth muscle layer, 78 our previous studies suggest that aberrant branching morphogenesis of the UB may also contribute to medullary defects observed in these mutants. 79 The possibility that medullary hypoplasia may be due in some cases to an intrinsic defect in medullary morphogenesis, rather than to urinary tract obstruction, is supported by the findings that Wnt7b-and Adamts 1/4-or Esrrg-null mice exhibit hypoplastic renal medulla at birth in the absence of structural abnormalities of the lower urinary tract.…”

Section: Do Not Distributementioning

confidence: 99%