The ‘who, where and when’ of neurogenesis during Drosophila melanogaster eye development

The development of structurally diverse and functionally complex multicellular organs is dependent on coupling the generation of cellular heterogeneity with structural organization. My thesis exploits the retina of the genetically tractable Drosophila melanogaster to address how organs develop from naïve tissues. During retinal development a wave of apical constriction, known as the morphogenetic furrow (MF), advances across the eye-disc epithelium as the leading front of photoreceptor (PR) differentiation. My thesis addresses three aspects of organogenesis from the perspective of neurogenesis: (1) ‘Who’ will develop as a PR? (2) ‘Where’ will neurogenesis initiate? (3) ‘When’ will neurogenesis occur? ‘Who?’ Neurogenesis begins with proneural factor expression, which assigns neural competence to naïve cells; this is coupled to MF progression in the retina. The Notch pathway refines neural competence to single evenly spaced PRs, in a process termed lateral inhibition. I identified nemo (nmo) as a target of proneural factors and show that Nmo promotes Notch-mediated lateral inhibition, thus contributing to the selection of single PRs and other neural cell types. ‘Where?’ A prerequisite to the initial onset of PR neurogenesis is regional-fate competence. Antennal/head fate selectors compete with and mutually antagonize eye-fate selectors to subdivide the tissue. Overlaid onto this are signalling pathways, which cooperate to promote MF initiation and neurogenesis. I find that compromising one of these pathways, the Ras/MEK/MAPK cascade, affects where neurogenesis initiates by regulating both regional-fate specification and signal transduction. This is achieved via factors that control extracellular ligand diffusion. ‘When?’ Although signalling pathways regulate gene expression to promote MF progression and neurogenesis, how this translates into epithelial morphogenesis is not known. I find that the MF’s pace is sensitive to integrin adhesion receptor levels, and that integrins are genetically downstream of the signalling events driving MF progression. Integrins within the MF stabilize microtubules to promote apical constriction and MF progression, thus genetically linking signalling events with cytoskeletal remodeling events necessary for morphogenesis and neurogenesis. My thesis supports the notion that cellular diversity follows from the interplay between signal transduction and cell competence, and that tissue structure is a consequence of signal transduction-regulated cell adhesion and cytoskeletal remodeling.