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Urogenital development in Pallister-Hall syndrome is disrupted in a cell-lineage-specific manner by constitutive expression of GLI3 repressor.
- Source :
-
Human molecular genetics [Hum Mol Genet] 2016 Feb 01; Vol. 25 (3), pp. 437-47. Date of Electronic Publication: 2015 Nov 24. - Publication Year :
- 2016
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Abstract
- Pallister-Hall syndrome (PHS) is a rare disorder caused by mutations in GLI3 that produce a transcriptional repressor (GLI3R). Individuals with PHS present with a variably penetrant variety of urogenital system malformations, including renal aplasia or hypoplasia, hydroureter, hydronephrosis or a common urogenital sinus. The embryologic mechanisms controlled by GLI3R that result in these pathologic phenotypes are undefined. We demonstrate that germline expression of GLI3R causes renal hypoplasia, associated with decreased nephron number, and hydroureter and hydronephrosis, caused by blind-ending ureters. Mice with obligate GLI3R expression also displayed duplication of the ureters that was caused by aberrant common nephric duct patterning and ureteric stalk outgrowth. These developmental abnormalities are associated with suppressed Hedgehog signaling activity in the cloaca and adjacent vesicular mesenchyme. Mice with conditional expression of GLI3R were utilized to identify lineage-specific effects of GLI3R. In the ureteric bud, GLI3R expression decreased branching morphogenesis. In Six2-positive nephrogenic progenitors, GLI3R decreased progenitor cell proliferation reducing the number of nephrogenic precursor structures. Using mutant mice with Gli3R and Gli3 null alleles, we demonstrate that urogenital system patterning and development is controlled by the levels of GLI3R and not by an absence of full-length GLI3. We conclude that the urogenital system phenotypes observed in PHS are caused by GLI3R-dependent perturbations in nephric duct patterning, renal branching morphogenesis and nephrogenic progenitor self-renewal.<br /> (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Subjects :
- Animals
Body Patterning genetics
Cell Proliferation
Disease Models, Animal
Embryo, Mammalian
Homeodomain Proteins genetics
Homeodomain Proteins metabolism
Humans
Hydronephrosis metabolism
Hydronephrosis pathology
Kidney metabolism
Kidney pathology
Kruppel-Like Transcription Factors metabolism
Mice
Mice, Knockout
Mutation
Nephrons abnormalities
Nephrons embryology
Nephrons metabolism
Nerve Tissue Proteins metabolism
Pallister-Hall Syndrome metabolism
Pallister-Hall Syndrome pathology
Phenotype
Signal Transduction
Stem Cells metabolism
Stem Cells pathology
Transcription Factors genetics
Transcription Factors metabolism
Ureter abnormalities
Ureter embryology
Ureter metabolism
Urogenital Abnormalities metabolism
Urogenital Abnormalities pathology
Zinc Finger Protein Gli3
Cell Lineage genetics
Gene Expression Regulation, Developmental
Hydronephrosis genetics
Kidney abnormalities
Kruppel-Like Transcription Factors genetics
Nerve Tissue Proteins genetics
Pallister-Hall Syndrome genetics
Urogenital Abnormalities genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1460-2083
- Volume :
- 25
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Human molecular genetics
- Publication Type :
- Academic Journal
- Accession number :
- 26604140
- Full Text :
- https://doi.org/10.1093/hmg/ddv483