ABSTRACT
Chromatin-remodeling complexes play critical roles in establishing gene expression patterns in response to developmental signals. How these epigenetic regulators determine the fate of progenitor cells during development of specific organs is not well understood. We found that genetic deletion of Brg1 (Smarca4), the core enzymatic protein in SWI/SNF, in nephron progenitor cells leads to severe renal hypoplasia. Nephron progenitor cells were depleted in Six2-Cre, Brg1flx/flx mice due to reduced cell proliferation. This defect in self-renewal, together with impaired differentiation resulted in a profound nephron deficit in Brg1 mutant kidneys. Sall1, a transcription factor that is required for expansion and maintenance of nephron progenitors, associates with SWI/SNF. Brg1 and Sall1 bind promoters of many progenitor cell genes and regulate expression of key targets that promote their proliferation.
Subject(s)
Cell Differentiation , Cell Proliferation , DNA Helicases/metabolism , Nephrons/embryology , Nuclear Proteins/metabolism , Stem Cells/metabolism , Transcription Factors/metabolism , Animals , COS Cells , Chlorocebus aethiops , DNA Helicases/genetics , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Mice , Mice, Transgenic , Nephrons/cytology , Nuclear Proteins/genetics , Stem Cells/cytology , Transcription Factors/geneticsABSTRACT
The formation of the proper number of nephrons requires a tightly regulated balance between renal progenitor cell self-renewal and differentiation. The molecular pathways that regulate the transition from renal progenitor to renal vesicle are not well understood. Here, we show that Sall1interacts with the nucleosome remodeling and deacetylase complex (NuRD) to inhibit premature differentiation of nephron progenitor cells. Disruption of Sall1-NuRD in vivo in knock-in mice (ΔSRM) resulted in accelerated differentiation of nephron progenitors and bilateral renal hypoplasia. Transcriptional profiling of mutant kidneys revealed a striking pattern in which genes of the glomerular and proximal tubule lineages were either unchanged or upregulated, and those in the loop of Henle and distal tubule lineages were downregulated. These global changes in gene expression were accompanied by a significant decrease in THP-, NKCC2- and AQP1-positive loop of Henle nephron segments in mutant ΔSRM kidneys. These findings highlight an important function of Sall1-NuRD interaction in the regulation of Six2-positive multipotent renal progenitor cells and formation of the loop of Henle.
Subject(s)
Loop of Henle/embryology , Loop of Henle/metabolism , Mi-2 Nucleosome Remodeling and Deacetylase Complex/metabolism , Multipotent Stem Cells/cytology , Organogenesis , Transcription Factors/metabolism , Amino Acid Sequence , Animals , Biomarkers/metabolism , Cell Differentiation/genetics , Cell Lineage/genetics , Cell Proliferation/genetics , Gene Expression Regulation, Developmental , Gene Ontology , Homozygote , Kidney Tubules/metabolism , Loop of Henle/abnormalities , Mice , Multipotent Stem Cells/metabolism , Mutation/genetics , Organogenesis/genetics , Protein Binding/genetics , Transcription Factors/chemistry , Ureter/embryology , Ureter/metabolismABSTRACT
The formation of the proper number of functional nephrons requires a delicate balance between renal progenitor cell self-renewal and differentiation. The molecular factors that regulate the dramatic expansion of the progenitor cell pool and differentiation of these cells into nephron precursor structures (renal vesicles) are not well understood. Here we show that Sall1, a nuclear transcription factor, is required to maintain the stemness of nephron progenitor cells. Transcriptional profiling of Sall1 mutant cells revealed a striking pattern, marked by the reduction of progenitor genes and amplified expression of renal vesicle differentiation genes. These global changes in gene expression were accompanied by ectopic differentiation at E12.5 and depletion of Six2+Cited1+ cap mesenchyme progenitor cells. These findings highlight a novel role for Sall1 in maintaining the stemness of the progenitor cell pool by restraining their differentiation into renal vesicles.