The normal course of growth and differentiation requires a complex and delicate set of controls to be sure that only the correct subset of cells receive the signal to divide and change. Many times, the signal is produced by one set of cells and diffuses to the recipient cells. One important group of diffusive signaling molecules is the Transforming Growth Factor Beta (TGF-beta) superfamily. Over forty members of this family have been identified and are responsible for pattern formation, tissue growth, bone morphogenesis and many other aspects of differentiation Members of this family are so conserved that Drosophila proteins have been shown to be substitutable for rat homologues in vivo. Interestingly, members of this family are also important for proper neurogenesis and prevention of neural degeneration. We have isolated a cDNA from Drosophila which encodes a putative TGF-beta. Northern blot analysis indicates two messages are produced, one is head-specific, the other is eye specific. We do not know if this is due to alternative splicing or two overlapping messages. The Open Reading Frame encodes a 310 amino acid protein, which is near the """"""""typical"""""""" size of this family. There is an RXXR signal sequence for cleavage at position 202, which is also the typical sequence and position for a TGF-beta. The putative active peptide which would be released by this cleavage shares 32% similarity with Porcine activin and 27% similarity with human TGF-beta 1. Although this seems low to identify a member of a family, the hallmark of the TGF-beta family is seven cysteines spaced in an invariant pattern. These cysteines are involved in formatting a structure found in the TGF-beta family, in members of the PDGF family and members of the NGF family called the cysteine knot. These cysteines, combined with some conserved Prolines and glycines clearly show that Z33 is a member of this important of signaling molecules. We will characterize the expression pattern of this gene throughout development. We will ascertain its function by generating flies with reduced or increased expression and seeing how the flies' physiology is altered with special attention focused on development in the eye. Since members of this family are evolutionarily conserved, it is very likely that a human homologue exists and whatever is learned about this gene in Drosophila will have direct bearing on human growth signaling and related diseases.
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