RESUMO
Congenital abnormalities of the kidney and the urinary tract (CAKUT) belong to the most common birth defects in human, but the molecular basis for the majority of CAKUT patients remains unknown. Here we show that the transcription factor SOX11 is a crucial regulator of kidney development. SOX11 is expressed in both mesenchymal and epithelial components of the early kidney anlagen. Deletion of Sox11 in mice causes an extension of the domain expressing Gdnf within rostral regions of the nephrogenic cord and results in duplex kidney formation. On the molecular level SOX11 directly binds and regulates a locus control region of the protocadherin B cluster. At later stages of kidney development, SOX11 becomes restricted to the intermediate segment of the developing nephron where it is required for the elongation of Henle's loop. Finally, mutation analysis in a cohort of patients suffering from CAKUT identified a series of rare SOX11 variants, one of which interferes with the transactivation capacity of the SOX11 protein. Taken together these data demonstrate a key role for SOX11 in normal kidney development and may suggest that variants in this gene predispose to CAKUT in humans.
Assuntos
Rim/anormalidades , Mutação , Fatores de Transcrição SOXC/genética , Ureter/anormalidades , Anormalidades Urogenitais/genética , Refluxo Vesicoureteral/genética , Animais , Caderinas/genética , Caderinas/metabolismo , Proliferação de Células , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética , Predisposição Genética para Doença , Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Humanos , Rim/metabolismo , Masculino , Camundongos Knockout , Morfogênese , Fenótipo , Fatores de Risco , Fatores de Transcrição SOXC/deficiência , Ureter/metabolismo , Anormalidades Urogenitais/metabolismo , Anormalidades Urogenitais/patologia , Refluxo Vesicoureteral/metabolismo , Refluxo Vesicoureteral/patologiaRESUMO
Congenital abnormalities of the kidney and urinary tract (CAKUT) are a highly diverse group of diseases that together belong to the most common abnormalities detected in the new-born child. Consistent with this diversity, CAKUT are caused by mutations in a large number of genes and present a wide spectrum of phenotypes. In this review, we will focus on duplex kidneys, a relatively frequent form of CAKUT that is often asymptomatic but predisposes to vesicoureteral reflux and hydronephrosis. We will summarise the molecular programs responsible for ureter induction, review the genes that have been identified as risk factors in duplex kidney formation and discuss molecular and cellular mechanisms that may lead to this malformation.