RESUMEN
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.
Asunto(s)
Linaje de la Célula/genética , Regulación del Desarrollo de la Expresión Génica , Hidronefrosis/genética , Riñón/anomalías , Factores de Transcripción de Tipo Kruppel/genética , Proteínas del Tejido Nervioso/genética , Síndrome de Pallister-Hall/genética , Anomalías Urogenitales/genética , Animales , Tipificación del Cuerpo/genética , Proliferación Celular , Modelos Animales de Enfermedad , Embrión de Mamíferos , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Hidronefrosis/metabolismo , Hidronefrosis/patología , Riñón/metabolismo , Riñón/patología , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Ratones Noqueados , Mutación , Nefronas/anomalías , Nefronas/embriología , Nefronas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Síndrome de Pallister-Hall/metabolismo , Síndrome de Pallister-Hall/patología , Fenotipo , Transducción de Señal , Células Madre/metabolismo , Células Madre/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Uréter/anomalías , Uréter/embriología , Uréter/metabolismo , Anomalías Urogenitales/metabolismo , Anomalías Urogenitales/patología , Proteína Gli3 con Dedos de ZincRESUMEN
Mutations in GLI3, a component of the Sonic Hedgehog (Shh) signaling pathway, cause a variety of human developmental syndromes. In this issue of the JCI, Cain and colleagues show that tightly regulated GLI3 repressor activity is essential for Shh-dependent differentiation of upper urinary tract pacemaker cells and the efficient flow of urine from the kidney to the bladder. These results link defective pacemaker cell differentiation with hydronephrosis and provide a cellular basis for one of the abnormal renal defects observed in humans with the GLI3-linked disease Pallister-Hall syndrome.