Regulation of Kidney Development by Shp2: An Unbiased Stereological Analysis

Abstract

Genes that regulate renal branching morphogenesis are likely to indirectly regulate nephron endowment, but few have been validated to do so in vivo. PTPN11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, acts downstream of receptor tyrosine kinases to modulate the Ras-MAPK pathway and has been implicated in branching morphogenesis in vitro and in invertebrates, and is therefore a candidate in vivo regulator of nephron number. In this work, heterozygous null mutant Shp2(+/-) mice at postnatal days 30-35 were compared with their wild-type (WT) littermates using unbiased stereology to determine if, indeed, the former had decreased nephron number due to their 50% decrease in gene/protein dosage. Although there was a trend toward decreases in total glomerular (nephron) number and kidney volume in Shp2(+/-) mice compared with WT, neither difference was statistically significant (11310 vs. 12198 glomeruli, P = 0.22; 62.8 mm(3) vs. 66.0 mm(3) renal volume; P = 0.40). We conclude that loss of 50% gene/protein dosage of PTPN11/Shp2 is insufficient to affect glomerular (and thereby nephron) number in mouse kidneys in vivo.