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Research Interests:
We have performed the functional analysis of Nerfin-1, a nuclear regulator of axon guidance required for a subset of early pathfinding events in the developing Drosophila CNS. Nerfin-1 belongs to a highly conserved subfamily of Zn-finger proteins. The neural precursor gene prospero is essential for nerfin-1 expression. Unlike nerfin-1 mRNA, which is expressed in many neural precursor cells, the encoded Nerfin-1 protein is only detected in the nuclei of neuronal precursors that will divide just once and then transiently in their nascent neurons. Although nerfin-1 null embryos have no discernible alterations in neural lineage development, CNS pioneering neurons require nerfin-1 function for early axon guidance decisions. Furthermore, nerfin-1 is required for the proper development of axon fascicles. Our studies also show that Nerfin-1 is essential for the proper expression of multiple genes whose encoded proteins participate in early axon guidance.
To better understand the regulation of nerfin-1 expression we have begun to characterize its cis-regulatory elements. An 11 kb nerfin-1 genomic fragment that contains 6 kb of upstream sequence serves to rescue a nerfin-1 null mutation. EvoPrinter analysis identifies multiple putative enhancer regions upstream of the transcribed region. Transgenic analysis of one of these regions reveals a neuroblast enhancer and of a second reveals a GMC and neuron enhancer. We have also identified enhancers for expression in the eye disc, in subsets of neurons, and in glia.
The nerfin-1 3’ UTR contains multiple predicted binding sites for microRNAs, and we have demonstrated that removal of the 3’ UTR releases the translational block in neuroblasts. To determine which miRNAs are regulating the expression of Nerfin-1 protein in neuroblasts, we are now generating transformant lines with constructs that contain subsets of the miRNA binding sites. So far our results reveal that multiple miRNAs play cooperative role in embryonic post-transcriptional regulation of nerfin-1 mRNA
Selected Publications:
- Odenwald WF, Rasband W, Kuzin A, Brody T (2005) EVOPRINTER, a multigenomic comparative tool for rapid identification of functionally important DNA, Proc Natl Acad Sci 102, 14700-5. Full Text/Abstract
- Kuzin A, Brody T, Moore AW, Odenwald WF (2005) Nerfin-1 is required for early axon guidance decisions in the developing Drosophila CNS, Dev Biol 277, 347-65. Full Text/Abstract
- Broihier HT, Kuzin A, Zhu Y, Odenwald W, Skeath JB (2004) Drosophila homeodomain protein Nkx6 coordinates motoneuron subtype identity and axonogenesis, Development 131, 5233-42. Full Text/Abstract
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