The Caenorhabditis elegans SEL-12 protein was shown to be not only structurally but also functionally similar to the human presenilins involved in Familial Alzheimer's disease.
sel-12 was initially identified as a suppressor of gain-of-function alleles of
lin-12/Notch in C. elegans [1]. Animals mutant for
sel-12 exhibit a highly penetrant egg laying defect (egl) and morphological abnormalities that lead to a grossly abnormal protruding vulva (p-vul). Anna Newman [2] has shown that some
sel-12 animals fail to specify the p cell fate correctly leading to a defective vulva uterine connection. However strains containing weaker
sel-12 alleles only show a weakly penetrant p-vul defect and are able to lay eggs, but become Egl and die of bagging later.This suggests that there might be additional defects responsible for the Egl defect. We have previously identified a functional defect of
sel-12 loss-of-function mutants in selected cholinergic neurons [3]. However,
sel-12 is broadly expressed both in neurons and in a variety of muscles at all developmental stages. Therefore we investigated whether the inability of
sel-12 animals to lay eggs is also caused by a neuronal defect. Pharmacological and epistasis tests revealed that
sel-12 animals behave like a muscle structure mutant. Using different GFP expression constructs that stain the vulva muscles, we are able to show that
sel-12 mutants indeed have several defects in their vulva muscles.
sel-12 mutant animals display a range of defects. Most animals exhibit misaligned, distorted vulva muscles but we also see muscles which have mismigrated or degenerated. Expression of the
sel-12 cDNA under the control of the
myo-3 and
unc-54 promoters does not rescue the Egl defect of
sel-12 which implies that
sel-12 activity is not required in mature vulva muscles but rather during their development. In hermaphrodites, the vulva muscles are derived from the M-lineage. By ablation it was shown that the loss of the vulva muscles is sufficient to cause an Egl defect. Expression of the
sel-12 cDNA only in the M-lineage fully rescues the Egl defect of
sel-12 mutants in all
sel-12 alleles tested so far. In contrast, the vulva structural defect that leads to a p-vul formation was not rescued by this construct. This clearly shows that these defects are independent from each other and can be separated. These data suggest that the different roles of
sel-12 during C .elegans development are complex and that
sel-12 affects various aspects of development in the nervous system, in muscles, and in epidermal structures. We are particularly interested in understanding the cross talk between the different structures involved in egg laying during their development. As
sel-12 was shown to facilitate
lin-12/Notch signaling we have further analyzed whether
lin-12 function is required for proper vulva muscle development. It is known that in a
lin-12 null allele the sex myoblasts (SM) that give rise to the sex muscles are converted into coelomocytes [4]. However in
lin-12(
n676930ts), a reduction of function mutant that is egl only at 25degC, the vulva muscles are present but display the same variety of defects found in a
sel-12 mutant. Therfore we conclude that
lin-12/Notch activety is required at various steps during sex myoblast development. This also suggests that
sel-12 is acting through
lin-12 to influence smooth muscle development in C. elegans. [1] Levitan and Greenwald (1995), Nature 377: 351-354. [2] 1999 International Worm Meeting [3] Wittenburg, Eimer, Lakowski, Roehrig, Rudolph and Baumeister (2000) Nature 406: 306-9 [4] Harfe, Branda, Krause, Stern and Fire (1998) Development 125: 2479-2488.