Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?

Abstract

BackgroundSchimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila.ResultsWe found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated β-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways.ConclusionsWe conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0519-7) contains supplementary material, which is available to authorized users.

Activation of podocyte Notch mediates early Wt1 glomerulopathy

“…These findings are consistent with previous reports demonstrating podocyte Notch activation in chemically induced models of glomerulosclerosis and in human biopsies of glomerular disease. 28 , 36 , 37 , 38 Increased podocyte Hes1 , Hes3 , Hes5 and Hey1 , Hey2, and HeyL have been found in streptozotocin- and puromycin aminonucleoside–induced glomerulosclerosis. 28 Podocyte apoptosis has been shown to play an instigating role in the pathogenesis of FSGS, and Notch activation in mature podocytes induces apoptosis.…”

Chromatin changes inSMARCAL1deficiency: A hypothesis for the gene expression alterations of Schimke immuno-osseous dysplasia

“…Observations in SIOD patient tissues have shown that a trait of interest can arise from either increased or decreased expression of key genes in tissues of SIOD patients. 7,20,21 Some gene expression changes appear to arise from effects of SMARCAL1 activity at promoters, 53 whereas others might arise from epigenetic changes induced by replication stress. Future genome-wide studies to assess the relationship between chromatin structure as well as epigenetic marks and gene expression will provide valuable insight into the mechanism by which SMAR-CAL1 deficiency alters gene expression.…”

“…The Drosophila Marcal1 and human SMARCAL1 overexpression screen was carried out at 28 C and has been previously described. 14,21 Drosophila have 5 longitudinal veins (L1, L2, L3, L4, and L5) as well as an anterior and posterior cross vein (ACV and PCV); overexpression of Marcal1 and SMARCAL1 leads to an ectopic vein parallel and anterior to L2, an ectopic vein extending laterally from the PCV, a partially missing or completely absent ACV or PCV, and distal bending or splitting of longitudinal veins L2, L4, and L5. 14,21 We screened for trxG and PcG alleles that lead to the suppression or enhancement of the ectopic wing veins induced by the overexpression of Marcal1 and SMARCAL1.…”

“…Ectopic wing veins observed in the F 1 progeny of the crosses were scored as previously published. 14,21 The reference wing vein phenotype was determined by crossing Marcal1 overexpression flies to w 1118 mutants of 3 genetic backgrounds; the scores from these crosses were averaged to provide a reference score. To determine whether there was any nonspecific interaction between the various mutant alleles and the GAL4-UAS system, all mutant lines were crossed to the C96-GAL4, UAS-Hrs/MKRS transgenic line and the degree of wing margin scalloping in the desired F 1 progeny was scored.…”

“…[15][16][17][18][19] The clinical features of SIOD appear to arise from pathological gene expression changes due to SMARCAL1 deficiency. 7,20,21 Interleukin 7 receptor a (IL7R) deficiency contributes to the T-cell immunodeficiency, elastin (ELN) deficiency to the arteriosclerosis, and Wnt and Notch overexpression to the renal disease. 7,20,21 The underlying mechanism for these gene expression alterations remains unclear.…”