The C.elegans
p53 homolog
cep-1 regulates a variety of cellular processes, including chromosome stability, DNA damage response, starvation, and low oxygen. We have identified a novel role for
cep-1 in the regulation of body size and find that
cep-1(
gk138) mutants, or wild type animals fed
cep-1(RNAi), are ~10% smaller than N2 adults. This Sma phenotype is greatly enhanced by treating early embryos to non-lethal episodes of anoxic stress or by inactivation of the
kri-1 gene. Combined inhibition of
cep-1 and
kri-1 by RNAi caused N2 adults to grow to only 73% of their normal length. Treating N2 embryos with anoxia or inactivation of
kri-1 alone does not affect body size, suggesting that
cep-1 and
kri-1/anoxia collaborate through parallel pathways to regulate size. We refer to this as a synthetic small (synSma) phenotype. To ask whether this synSma phenotype was manifested through TGF signaling we carried out epistasis analysis. Mutations in
lon-1 cause a long body size phenotype that is suppressed by mutations in upstream components[1, 2]. We found that
cep-1;
lon-1 double mutants were of intermediate body size, and inhibition of both
cep-1 and
kri-1 reduced the size of
lon-1 mutants to untreated N2 lengths. Because the combined inhibition of
cep-1 and
kri-1 did not cause
lon-1 mutants to become as small as N2 animals under the same conditions, we suggest that
cep-1/kri-1 signal downstream or in parallel with the TGF pathway. Seam cell numbers in
cep-1/kri-1 adults are the same as N2 but are smaller in size. Sma animals are fertile, move well and respond to touch. Therefore, the decreased body size in these animals is likely due to decreased cell size not cell number. Inhibition of
cep-1 and
kri-1 in two different
sma-3 alleles caused ~30% embryonic and ~10% adult lethality, but did not cause lethality in
lon-1 mutants. To our surprise we found that the surviving
sma-3 animals in which
cep-1 and
kri-1 were inactivated grew to larger adult body sizes (1144 16m) compared with untreated
sma-3 mutants (1052 20m, P< 0.001), suggesting that
cep-1 and
kri-1 may impinge on a feedback signal with the TGF pathway. These studies should provide insight into how cell size is regulated by Krit1 and
p53. References .1.Maduzia, L.L., et al.., Dev. Biol., 2002. 246: 418-28. 2.Morita, K., et al., Embo J, 2002. 21: 1063-73.