Urogenital development in Pallister–Hall syndrome is disrupted in a cell-lineage-specific manner by constitutive expression of GLI3 repressor

Blake, Joshua; Hu, Di; Cain, Jason; Rosenblum, Norman D.

doi:10.1093/hmg/ddv483

Cited by 25 publications

(26 citation statements)

References 27 publications

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“…Our results are similar to the research on gain-or loss-of-functional mutants for Shh-Gli signaling [Cain et al, 2009[Cain et al, , 2011Haraguchi et al, 2012;Blake et al, 2016]. That research revealed that Shh-Gli signaling plays a major role in the metanephric collecting duct system during kidney and urogenital system development.…”

Section: Discussionsupporting

confidence: 91%

“…Intriguingly, deletion of both Gli3 and Shh rescues the renal phenotype observed in Shh conventional mutants as well as the expression of Pax2, Sall1, Cyclin D1, N-Myc, Gli1, and Gli2 [Gill and Rosenblum, 2006]. Inappropriate activation of the Shh-Gli signaling pathways occurs in several human cancers [Ok et al, 2012] and renal malformations [Pallister et al, 1989;Tsanev et al, 2009;McPherson and Cold, 2013;Blake et al, 2016]. Genetic elimination of Ptc1 in the ureteric cell lineage resulted in increased ectopic Shh signaling activity in the cortical collecting ducts and the UB tips of the developing kidney.…”

Section: Discussionmentioning

confidence: 97%

“…That research revealed that Shh-Gli signaling plays a major role in the metanephric collecting duct system during kidney and urogenital system development. Based on the reported studies [Cain et al, 2009[Cain et al, , 2011Haraguchi et al, 2012;Blake et al, 2016], sustained Smo activity upregulated the Ptch1 expression of the renal collecting ducts and increased Ptch1 may disrupt the Gli transcription activator/Gli3 repressor (Gli3R) balance. As a result, the differentiation of cells is reduced and hydronephrosis is induced.…”

Section: Discussionmentioning

confidence: 99%

“…Also, it is well known that Pallister-Hall syndrome (PHS) is caused by a genetic mutation of Gli3 that produces the transcriptional repressor Gli3R [Pallister et al, 1989]. Urogenital malformation in PHS exhibits renal aplasia, renal hypoplasia, and hydroureter [Pallister et al, 1989;Tsanev et al, 2009;McPherson and Cold, 2013;Blake et al, 2016]. Studies using mutant mice with Gli3R and Gli3 null alleles have demonstrated that Gli3R alters the normal Shh signaling domain in the caudal embryo and that Gli3R impairs nephric duct patterns, renal branching morphogenesis, and nephrogenic mesenchyme self-renewal.…”

Section: Discussionmentioning

confidence: 99%

“…Studies using mutant mice with Gli3R and Gli3 null alleles have demonstrated that Gli3R alters the normal Shh signaling domain in the caudal embryo and that Gli3R impairs nephric duct patterns, renal branching morphogenesis, and nephrogenic mesenchyme self-renewal. Also it has been demonstrated that urogenital system development in PHS depends on increased levels of Gli3R [Blake et al, 2016]. Taken together, these findings suggest that Gli transcription activator/ Gli3R balance may be a critical factor during the development of the kidney and ureter, and disruption of the Gli transcription activator/Gli3R balance including genetic eliminations of Ptc1 and Smo, and constitutive activation of Smo, may lead to renal hypoplasia, hydronephrosis, and hydroureter via a decrease in ureteric mesenchyme and changing gene expression.…”

Section: Discussionmentioning

confidence: 99%

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Constitutive Activation of Smoothened in the Renal Collecting Ducts Leads to Renal Hypoplasia, Hydronephrosis, and Hydroureter

Gupta

Hwang

Cho

et al. 2017

Cells Tissues Organs

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Sonic Hedgehog (Shh) signaling plays a major role in and is essential for regulation, patterning, and proliferation during renal development. Smoothened (Smo) plays a pivot role in transducing the Shh-glioma-associated oncogene Kruppel family member. However, the cellular and molecular mechanism underlying the role of sustained Smo activation in postnatal kidney development is still not clearly understood. Using a conditional knockin mouse model that expresses a constitutively activated form of Smo (SmoM2) upon Homeobox-B7-mediated recombination (Hoxb7-Cre), the effects of Shh signaling were determined in postnatal kidney development. SmoM2;Hoxb7-Cre mutant mice showed growth retardation with a reduction of body weight. Constitutive activation of Smo in the renal collecting ducts caused renal hypoplasia, hydronephrosis, and hydroureter. The parenchymal area and glomerular numbers were reduced, but the glomerular density was increased in SmoM2;Hoxb7-Cre mutant mice. The expression of Patched 1, the receptor of Shh and a downstream target gene of the Shh signaling pathway, was highly restricted and it was upregulated in the inner medullary collecting ducts of the kidney. The proliferative cells in the mesenchyme and collecting ducts were decreased in SmoM2;Hoxb7-Cre mutant mice. This study showed for the first time that sustained Smo inhibits postnatal kidney development by suppressing the proliferation of the mesenchyme and medullary collecting ducts in mice.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Constitutive Activation of Smoothened in the Renal Collecting Ducts Leads to Renal Hypoplasia, Hydronephrosis, and Hydroureter

Gupta

Hwang

Cho

et al. 2017

Cells Tissues Organs

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Pallister‐Hall syndrome, GLI3, and kidney malformation

McClelland

Rosenblum

2022

American J of Med Genetics Pt C

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Pallister-Hall syndrome (PHS) is a rare autosomal dominant disease diagnosed by the presence of hypothalamic hamartoma, mesoaxial polydactyly and a truncating variant in the middle third of the GLI-Kruppel family member 3 (GLI3) gene. PHS may also include a wide range of clinical phenotypes affecting multiple organ systems including congenital anomalies of the kidney and urinary tract (CAKUT). The observed clinical phenotypes are consistent with the essential role of GLI3, a transcriptional effector in the hedgehog (Hh) signaling pathway, in organogenesis. However, the mechanisms by which truncation of GLI3 in PHS results in such a variety of clinical phenotypes with variable severity, even within the same organ, remain unclear. In this study we focus on presentation of CAKUT in PHS. A systematic analysis of reported PHS patients (n = 78) revealed a prevalence of 26.9% (21/78) of CAKUT. Hypoplasia (± dysplasia) and agenesis were the two main types of CAKUT; bilateral and unilateral CAKUT were reported with equal frequency. Examination of clinical phenotypes with CAKUT revealed a significant association between CAKUT and craniofacial defects, bifid epiglottis and a Disorder of Sex Development, specifically affecting external genitalia. Lastly, we determined that PHS patients with CAKUT predominately had substitution type variants (as opposed to deletion type variants in non-CAKUT PHS patients) in the middle third of the GLI3 gene. These results provide a foundation for future work aimed at uncovering the molecular mechanisms by which variant GLI3 result in the wide range and severity of clinical features observed in PHS.

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Hedgehog signalling in Foxd1+ embryonic kidney stromal progenitors controls nephron formation via Cxcl12 and Wnt5a

D'Cruz,

Kim,

Mulder

et al. 2023

The Journal of Pathology

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Congenital anomalies of the kidney and urinary tract (CAKUT) are characterised by a spectrum of structural and histologic abnormalities and are the major cause of childhood kidney failure. During kidney morphogenesis, the formation of a critical number of nephrons is an embryonic process supported, in part, by signalling between nephrogenic precursors and Foxd1‐positive stromal progenitor cells. Low nephron number and abnormal patterning of the stroma are signature pathological features among CAKUT phenotypes with decreased kidney function. Despite their critical contribution to CAKUT pathogenesis, the mechanisms that underlie a low nephron number and the functional contribution of a disorganised renal stroma to nephron number are both poorly defined. Here, we identify a primary pathogenic role for increased Hedgehog signalling in embryonic renal stroma in the genesis of congenital low nephron number. Pharmacologic activation of Hedgehog (Hh) signalling in human kidney organoid tissue decreased the number of nephrons and generated excess stroma. The mechanisms underlying these pathogenic effects were delineated in genetic mouse models in which Hh signalling was constitutively activated in a cell lineage‐specific manner. Cre‐mediated excision of Ptch1 in Foxd1+ stromal progenitor cells, but not in Six2+ nephrogenic precursor cells, generated kidney malformation, identifying the stroma as a driver of low nephron number. Single‐cell RNA sequencing analysis identified Cxcl12 and Wnt5a as downstream targets of increased stromal Hh signalling, findings supported by analysis in human kidney organoids. In vivo deficiency of Cxcl12 or Wnt5a in mice with increased stromal Hh signalling improved nephron endowment. These results demonstrate that dysregulated Hh signalling in embryonic renal stromal cells inhibits nephron formation in a manner dependent on Cxcl12 and Wnt5a. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Urogenital development in Pallister–Hall syndrome is disrupted in a cell-lineage-specific manner by constitutive expression of GLI3 repressor

Cited by 25 publications

References 27 publications

Constitutive Activation of Smoothened in the Renal Collecting Ducts Leads to Renal Hypoplasia, Hydronephrosis, and Hydroureter

Constitutive Activation of Smoothened in the Renal Collecting Ducts Leads to Renal Hypoplasia, Hydronephrosis, and Hydroureter

Pallister‐Hall syndrome, GLI3, and kidney malformation

Hedgehog signalling in Foxd1+ embryonic kidney stromal progenitors controls nephron formation via Cxcl12 and Wnt5a

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