BIOLOGICAL OVERVIEW

The R7 photoreceptor is the last of eight photoreceptors to develop in each ommatidium of the compound eye. In sina mutants, ommatidial development proceeds normally up to the stage when a cell fills the R7 precursor position within each ommatidium, contacting R1, R6 and R8, and its nuclei joins the nuclei of the two cone cells in the apical (sunken) region of the epithelium. From this point onward, development proceeds abnormally. Instead of sinking into the epithelium to join the other photoreceptor cell nuclei, the nucleus of the cell in the R7 position remains in the apical region of the epithelium, assuming the position of an equatorial cone cell nucleus. It has the characteristic morphology of an equatorial cone cell and yet it retains its contacts with R1, R6 and R8 deeper in the ommatidium, reflecting its initial position as the R7 precursor. Later the cell maintains its equatorial cone cell morphology but loses its contacts with the R1, R6 and R8, and completely assumes the equatorial cone cell position. In sina mutants the R7 position cell exhibits no evidence of axon outgrowth and does not possess neural specific markers. The observed developmental defects are indistinguishable from those observed in sevenless mutants (Carthew, 1990).

Is the induction of sina expression a consequence of sevenless activity? Eye discs from sevenless mutant larvae were stained with SINA antibody, and the staining pattern was found to be indistinguishable from wild type. A similar result was found in boss mutant eye discs. Thus, these genes do not appear to regulate expression of sina in any cell, including the R7 precursor (Carthew, 1990). Nevertheless, SINA is a target of the Boss-Sevenless-Ras1 pathway (Dickson, 1992). Thus the activity of sina is regulated by the Sevenless pathway, but regulation of its transcription is independent of that pathway.

What biochemical role does SINA play in R7 fate? Prospero has been identified as a potential target of SINA. The sequence of SINA suggests that it is a transcription factor, or interacts with chromatin, two of the functions ascribed to RING finger proteins. SINA interacts physically with Phyllopod, a nuclear factor that is induced by Sevenless signals. Both factors are involved in a secondary pathway for upregulating transcription of the prospero gene. The Pointed-Yan pathway however, is sufficient for upregulating prospero and makes the SINA-Prospero pathway redundant (Kauffmann, 1996).

There are several other clues as to SINA function. It is upregulated during late neurogenesis and its transcription in the eye appears to be cell cycle regulated. In vertebrates there is a highly conserved SINA homolog thought to function downstream of p53 with a role in suppression of cell proliferation, in apoptosis and in tumor suppression (Amson, 1996 and Nemani, 1966).

Evidence for an interaction between mammalian Sina homologs (termed Siah proteins) and DCC (deleted in colorectal cancer) suggests that Sina/Siah functions to regulate protein concentrations via the ubiquitin-protease pathway, and draws into question the classification of Sina as a transcripiton factor. DCC is postulated to function as transmembrane receptor for the axon and cell guidance factor netrin-1 (see Drosophila Netrins). DCC cytoplasmic domain binds to proteins encoded by mammalian homologs of the Drosophila seven in absentia (sina) gene, as well as to Drosophila Sina protein. Immunofluorescence studies suggest the Sina/Siah proteins localize predominantly in the cytoplasm and in association with DCC. DCC is found to be ubiquitinated (chemically modified to promote degradation); the Sina/Siah proteins regulate DCC's level of expression. Proteasome inhibitors block the effects of Sina/Siah on DCC, and the Sina/Siah proteins interact with ubiquitin-conjugating enzymes (Ubcs). A mutant Siah protein, lacking the amino-terminal Ubc-binding sequences, complexes with DCC, but does not degrade it. The in vivo interaction between Sina/Siah and DCC was confirmed through studies of transgenic Drosophila lines in which DCC and Sina were ectopically expressed in the eye. Ectopic expression of human DCC in the developing eye interfers with Sina function and cause R7 defects. Taken together, the data imply that the Sina/Siah proteins regulate DCC (and perhaps other proteins) via the ubiquitin-proteasome pathway (Hu, 1997).

GENE STRUCTURE

In Drosophila melanogaster, the sina gene is located within an intron of the Rh4 opsin gene. The nucleotide sequences and chromosomal arrangements of these genes were also studied in Drosophila virilis. An interspecies comparison between D. melanogaster and D. virilis reveals that the protein-coding sequences of the sina and Rh4 genes are highly conserved, but the relative chromosomal position and structural arrangement of these genes differ between the two species. In particular, the sina and Rh4 genes are widely separated in D. virilis, and there is no intron in the Rh4 gene. The Rh4 gene was probably translocated to another chromosomal location by a retrotransposition event (Neufeld, 1992).

Bases in 5' UTR - 902

Exons - 2

Bases in 3' UTR - 1128 and 1288

PROTEIN STRUCTURE

Amino Acids - 315

Structural Domains

The protein is hydrophilic. The N-terminal 60 amino acids are marked by a highly basic region, while the C-terminal 50 amino acids possess an overall acidic charge. The N-terminal is a cysteine-rich region in which seven cysteines and a histidine form a pattern with extensive similarity to the protein product of the DG17 gene of Dictyostelium. The slime mold gene is specifically induced by cAMP during aggregation (Carthew, 1990).

date revised: 20 June 98

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