Academic journal article Genetics

HOP-1 Presenilin Deficiency Causes a Late-Onset Notch Signaling Phenotype That Affects Adult Germline Function in Caenorhabditis Elegans

Academic journal article Genetics

HOP-1 Presenilin Deficiency Causes a Late-Onset Notch Signaling Phenotype That Affects Adult Germline Function in Caenorhabditis Elegans

Article excerpt

PARALOGOUS genes often display functional redundancy, whereby the gene products perform overlapping functions. Evolutionary theory suggests that slight differences in function and/or expression could explain the maintenance of apparent genetic redundancy (Thomas 1993; Nowak et al. 1997), but experimental dissection of functional differences between redundant genes is complicated by the similarity of their mutant phenotypes. Here, we address the apparent functional redundancy of two Caenorhabditis elegans presenilin genes, sel-12 and hop-1, which share 50% amino acid similarity and 31% amino acid identity. These presenilin paralogs have been conserved since at least the origin of the Caenorhabditis clade, divergence within which is comparable to the divergence across the chordate phylum (Kiontke et al. 2004). Other animal species, including humans, also maintain two presenilin paralogs that exhibit partial genetic redundancy, raising the interesting possibility of molecular specialization that could be afforded by two alternative presenilin subunits for the g secretase complex. Differences in gene expression and mutant phenotypes for the two mouse presenilin genes suggest that mammalian presenilin redundancy has been preserved through the existence of unique roles for each presenilin in addition to their common roles, but little is known about the division of labor between these two genes with regard to specific cellular events that require presenilin function (Lee et al. 1996; Donoviel et al. 1999; Herreman etal. 1999).

An essential cellular role of presenilin proteins is to mediate the final activation step in the Notch signaling pathway by catalyzing the intramembranous cleavage of the Notch Receptor in cells that respond to Notch ligand [for review see Kopan and Ilagan (2009)]. The presenilin protein is the catalytic subunit of g secretase, the large membrane-resident enzyme that mediates this proteolytic cleavage and consists of four essential subunits in a 1:1:1:1 stoichiometry [for review see Zhang et al. (2014)]. In C. elegans, the presenilin subunit is the only one that is encoded by two alternative gene paralogs. Since all Caenorhabditis species have conserved a sel-12 and a hop-1 ortholog, there must be evolutionary pressure to maintain both genes. It is possible that both genes contribute additively to the overall amount of presenilin needed in a cell, or that the two presenilins may have unique functions in addition to their overlapping functions. Until now, analysis of sel-12 and hop-1 mutants has identified unique roles for the sel-12 presenilin, but none for hop-1, leaving the existence of the hop-1 presenilin a mystery.

Multiple Notch signaling events and their biological outcomes are well characterized throughout C. elegans development. On this foundation, the SEL-12 and HOP-1 presenilins provide a tractable system in which to compare the contributions of two presenilin proteins in vivo (Li and Greenwald 1997; Westlund etal. 1999).The sel-12 and hop-1 genes have been found to be largely genetically redundant, in that Notch signaling can be mediated by either presenilin, but is blocked if both presenilins are absent. Thus, hop-1 ; sel-12 double mutants display a collection of mutant phenotypes that correspond to loss-of-function Notch phenotypes. For example, hop-1; sel-12 homozygous hermaphrodites display maternaleffect embryonic lethality similar to that caused by hypomorphic mutations in the glp-1 /Notch receptor. These double mutants also display a severe egg-laying defect characterized by the lack of ventral uterine cell fate induction in the somatic gonad, similar to that caused by null mutations in the lin-12/ Notch receptor. Furthermore, hop-1; sel-12 homozygotes that also lack maternally supplied sel-12 display the stark germline sterility that is observed in glp-1/Notch null mutants, in which germ cells fail to proliferate and instead enter meiosis prematurely (Li and Greenwald 1997; Westlund etal. …

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