An important control point in meiotic development is the transition from pachytene to diplotene/diakinesis ( P achytene EX it) which involves the nuclear events of disassembly of the synaptonemal complex, chiasma formation, chromosome condensation and the differentiation events of oocyte cellularization and growth. Mutations that disrupt this transition show a Pex phenotype where nuclei arrest in pachytene and clump, and there is a loss of the hexagonal packing of cells along the gonadal surface distal to the loop. Previous work demonstrated that mutations in RAS/MAP kinase pathway genes show Pex and vulvaless phenotypes (1). Genetic screens have identified additional Pex mutations. Two mutations, with no obvious somatic defects, were found to be allelic to
let-21(
e1778) , originally identified by E. Hedgecock. Positional cloning identified
let-21 as T19E10.1, a homolog of the proto-oncogene
ect2 . LET-21 and
ect2 both have two N-terminal BRCT related domains, first described in the breast cancer protein BRCA1 and certain cell cycle checkpoint genes (2). Both have a centrally located DH domain (~200aa) and its associated PH domain (~100aa) that function as guanine nucleotide exchange factors (GNEF) for Rho-family GTPases which have been implicated in control of the cytoskeleton (3). Truncation of
ect2 , removing both BRCT domains, results in transformation of fibroblasts in vitro (4) suggesting that the BRCT domains may in some way negatively regulate the GNEF activity. A role for
let-21 in cell cycle progression is suggested by the sterile unc (Stu) phenotype of
e1778 . Two internal deletion alleles were identified that are likely null and show a more pronounced Stu phenotype where only rudimentary gonads are formed. A role for
let-21 in cytoskeletal organization is suggested by the cellular and cytoplasmic disorganization observed in mutant germlines. LET-21 may function to coordinate nuclear and cytoplasmic activities during both the mitotic and meiotic cell cycle. 1) Church et al. '95, Dev 121:2525; 2) Bork et al. '97, FASEB J 11:68; 3) Soisson et al. '98, Cell 95:259; 4) Miki et al. '93, Nature 362:462