C-terminal binding protein

DEVELOPMENTAL BIOLOGY

Developmental Northern analysis of wild-type flies using the CtBP two-hybrid insert as a probe shows that three major transcripts (2.5, 2.7 and 4.0 kb) are expressed dynamically throughout all stages of development, whereas an additional 3.5 kb transcript is detected predominantly in adult females and embryos stages. CtBP transcript levels increase both early, during oogenesis and embryogenesis, and later in pre-pupae stages. CtBP expression is detected ubiquitously in the germarium and early oogenic stages and is highly expressed in nurse cells by stage 10. This transcript is dumped into the oocyte and is detected ubiquitously as a maternal transcript in early and cellular blastoderm stage embryos (Poortinga, 1998).

Effects of Mutation or Deletion

It has been demonstrated that CtBP is essential for proper embryonic segmentation by analyzing embryos lacking maternal CtBP activity. While hairy is probably not the only segmentation gene interacting with CtBP, dose-sensitive genetic interactions exist between CtBP and hairy mutations (Poortinga, 1998).

The P1590 strain carries a homozygous lethal insertion, with the homozygotes dying as pharate adults. When dissected from their pupal cases, CtBP/1590 homozygotes exhibit duplicated and ectopic bristles (macrochaetes) on the notum and scutellum. The P1590 strain also exhibits a strong maternal effect phenotype. It was on the basis of its maternal requirement that the P-1590 allele was identified in a screen for maternal-effect lethals. In this screen, a change of function mutation in an RNA polymerase II subunit (wimp) was used to reduce, but not eliminate, P-1590 maternal contribution. Embryos derived from mothers trans-heterozygous for wimp and the P1590 allele die, and cuticle preparations of these embryos show segmentation defects, ranging from pair-wise fusions of adjacent denticle bands to more widespread denticle fusions (Poortinga, 1998).

Since wimp reduces, but does not eliminate maternal function, loss of CtBP/P1590 function in germline clones was examined using the FLP-DFS technique. The FLP-DFS system incorporates the presence of a dominant female sterile (DFS) mutation, ovo^D1, and the FLP-FRT yeast site-specific recombination system to create germline-specific mosaics. A P1590 FRT82B chromosome had been generated previously as part of a screen using the FLP-DFS technique to look for maternal phenotypes in zygotic single P-element-induced mutations. Embryos derived from germline clones generated with this chromosome were reported to have segmentation defects resulting in pair-wise fusions, as well as large holes in the ventral cuticle (Perrimon, 1996). Using this P1590 FRT82B stock, more severe cuticle disruptions have been obtained than previously reported: embryos were consistently observed that are significantly shorter than wild-type, with either 'lawns' of denticles on the ventral cuticle or severely fused or missing denticle bands (Poortinga, 1998).

If the segmentation defects observed in embryos lacking maternal CtBP are due to its interaction with Hairy, disruptions in patterning similar to those found in hairy mutations or loss of maternal Groucho are expected. In particular, the expression of the other primary pair-rule genes are expected to be disrupted and fushi tarazu expression to be derepressed. Consistent with this, Ftz stripes are found to be expanded in embryos lacking maternal CtBP. However, this broad band of expression later resolves into stripe-specific ftz repression, with stripes 2, 4, 5 and 6 predominantly affected. Aberrant expression of the primary pair-rule gene proteins, Eve and Runt, as well as of Hairy itself are also observed. Since the primary pair-rule genes respond directly to gap gene cues, gap gene expression was examined in embryos lacking maternal CtBP. Expression of the three gap genes examined, Hunchback, Krüppel and Knirps, appears normal in these embryos. In addition to its effects on anterior-posterior patterning, embryos lacking maternal CtBP also show disruptions of dorsoventral patterning. Beginning with the expression of the pair-rule genes, a lack of segmentation gene expression is detected on the ventral surface (Poortinga, 1998).

In addition to the disruption of patterning in P1590 germline clones, CtBP/P1590 was examined for genetic interaction with hairy. h mutations result in a range of cuticle phenotypes from loss or fusion of adjacent denticle bands to a fusion of most of the segments ('lawn' phenotype), with the most common phenotype called the classic pair-rule phenotype that results from the loss of alternating segment-wide regions. Larvae homozygous for a strong h allele, h^7H, display the extreme 'lawn' phenotype, whereas larvae trans-heterozygous for the h^7H allele and a weaker h allele, h^12C, display the classic pair-rule phenotype. This h^7H/h^12C allelic combination was initially used to examine if reducing the CtBP dose maternally would suppress or enhance the intermediate pair-rule phenotype. P1590 was genetically recombined onto a chromosome containing the h^7H allele. Reducing the dose of CtBP maternally results in the suppression of the h^7H/h^12C mutant cuticle phenotype. Likewise, reducing the dose of CtBP maternally in the severe h^7H background suppresses the extreme lawn phenotype. No alterations in viability or phenotype of any progeny classes are observed when P1590 is trans-heterozygous with h^7H, or when the h^7H P1590 recombinant chromosome is crossed to wild-type (Poortinga, 1998).

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