Hamartin regulates cessation of mouse nephrogenesis independently of Mtor.

Abstract

Nephrogenesis concludes by the 36th week of gestation in humans and by the third day of postnatal life in mice. Extending the nephrogenic period may reduce the onset of adult renal and cardiovascular disease associated with low nephron numbers. We conditionally deleted either <i>Mtor</i> or <i>Tsc1</i> (coding for hamartin, an inhibitor of Mtor) in renal progenitor cells. Loss of one <i>Mtor</i> allele caused a reduction in nephron numbers; complete deletion led to severe paucity of glomeruli in the kidney resulting in early death after birth. By contrast, loss of one <i>Tsc1</i> allele from renal progenitors resulted in a 25% increase in nephron endowment with no adverse effects. Increased progenitor engraftment rates ex vivo relative to controls correlated with prolonged nephrogenesis through the fourth postnatal day. Complete loss of both <i>Tsc1</i> alleles in renal progenitors led to a lethal tubular lesion. The hamartin phenotypes are not dependent on the inhibitory effect of TSC on the Mtor complex but are dependent on Raptor.