The long-term goal of this project is a detailed understanding of how neural cell fates are specified in the ectoderm of developing animals. In all species that have been studied, this process depends on the activity of """"""""proneural"""""""" genes, which encode a distinctive family of basic helix-loop-helix transcriptional activator proteins. Our recent preliminary studies in Drosophila have revealed the existence of novel modes of regulation of the proneural genes (both transcriptional and post-transcriptional), and have defined a set of very interesting genes that are expressed downstream of the proneurals during adult peripheral nervous system (PNS) development. This project has three major objectives, all focused on the regulation and function of proneural gene activity: (1) Investigate the functional relationship between proneural genes and Notch-mediated lateral inhibition. (2) Investigate novel modes of post-transcriptional regulation of proneural gene activity. (3) Investigate the function and regulation of genes that act downstream of proneural genes. The Drosophila adult PNS (where the existence of the proneural genes was first revealed genetically-nearly a century ago) remains, we think, a particularly advantageous venue in which to study these key cell fate determinants. Nevertheless, the results of this project may be expected to have significance well beyond the particular setting of the fly PNS. Of particular importance is the observation that a broad spectrum of human tumors with a """"""""neuroendocrine"""""""" phenotype are associated with strong overexpression of proneural genes, including small cell lung cancer (the most lethal form of lung cancer) and neuroblastoma (an aggressive childhood cancer). By elucidating both transcriptional and post-transcriptional mechanisms that normally regulate proneural gene activity negatively, our work may offer important insight into the pathogenesis of these diseases. By helping to illuminate shared mechanisms of neurogenesis, we also expect to contribute substantially to our broad understanding of how animals build their nervous systems.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Development - 1 Study Section (DEV)
Program Officer
Tompkins, Laurie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
Zip Code
Miller, Steven W; Posakony, James W (2018) Lateral inhibition: Two modes of non-autonomous negative autoregulation by neuralized. PLoS Genet 14:e1007528
Smith, Andrew F; Posakony, James W; Rebeiz, Mark (2017) Automated tools for comparative sequence analysis of genic regions using the GenePalette application. Dev Biol 429:158-164
Miller, Steven W; Rebeiz, Mark; Atanasov, Jenny E et al. (2014) Neural precursor-specific expression of multiple Drosophila genes is driven by dual enhancer modules with overlapping function. Proc Natl Acad Sci U S A 111:17194-9
Liu, Feng; Posakony, James W (2014) An enhancer composed of interlocking submodules controls transcriptional autoregulation of suppressor of hairless. Dev Cell 29:88-101
Hirono, Keiko; Margolis, Jonathan S; Posakony, James W et al. (2012) Identification of hunchback cis-regulatory DNA conferring temporal expression in neuroblasts and neurons. Gene Expr Patterns 12:11-7
Rebeiz, Mark; Castro, Brian; Liu, Feng et al. (2012) Ancestral and conserved cis-regulatory architectures in developmental control genes. Dev Biol 362:282-94
Liu, Feng; Posakony, James W (2012) Role of architecture in the function and specificity of two Notch-regulated transcriptional enhancer modules. PLoS Genet 8:e1002796
Rebeiz, Mark; Miller, Steven W; Posakony, James W (2011) Notch regulates numb: integration of conditional and autonomous cell fate specification. Development 138:215-25
Miller, Steven W; Avidor-Reiss, Tomer; Polyanovsky, Andrey et al. (2009) Complex interplay of three transcription factors in controlling the tormogen differentiation program of Drosophila mechanoreceptors. Dev Biol 329:386-99
Schweisguth, F; Nero, P; Posakony, J W (1994) The sequence similarity of the Drosophila suppressor of hairless protein to the integrase domain has no functional significance in vivo. Dev Biol 166:812-4

Showing the most recent 10 out of 13 publications