A central goal of developmental biology is to understand the gene expression programs and signal transduction pathways that regulate cell fate decisions and cellular differentiation in developing tissues. The long-term objective of our research is to investigate the developmental regulation and functions of AP-2 transcription factors. In mammals, AP-2 family members (AP-2a, AP-2/3 and AP-2g) have essential roles in development and are implicated as tumor suppressors in breast and ovarian carcinomas and melanoma. We identified dAP-2, the sole Drosophila melanogaster homolog of mammalian AP-2 family genes, in order to use the versatile tools of Drosophila genetics to establish regulatory paradigms for AP-2. Our recent unpublished data including analysis of dAP-2 null and partial loss of function mutants and analysis of dAP-2 expression in leg imaginal discs mosaic for mutations in various Notch signaling components, lead us to hypothesize that dAP-2 is a critical target of Notch signaling during leg and central nervous system development. The nervous system defects, reduced proboscis and severely shortened legs of dAP-2 null mutant flies correlate strikingly with nervous system, craniofacial, and limb defects seen in AP-2cx knock-out mice indicating that AP-2 family functions have been fundamentally conserved between flies and mice. We propose to examine the dependency of dAP-2 expression on Notch signaling in the limb imaginal disc during larval and pupal stages and in procephalic neuroectoderm during embryogenesis using a combination of genetic and molecular approaches including loss- and gain-of-function genetic analyses, immunostaining, and mapping of dAP-2 cis regulatory elements. The proposed research will significantly advance our understanding of AP-2 regulation during limb and nervous system development, and refine our understanding of how Notch signaling is interpreted in different tissues. In addition this work may shed light on how mis-regulation of AP-2 factors contributes to loss of growth control leading to cancer.
| Ahn, Youngwook; Zou, Jizhong; Mitchell, Pamela J (2011) Segment-specific regulation of the Drosophila AP-2 gene during leg and antennal development. Dev Biol 355:336-48 |
