Precise control of neuronal specification is a prerequisite for the formation of a highly complex nervous system. Moreover, nervous system injury and degeneration involves a loss of specific groups of neurons, and therefore, understanding the mechanisms underlying neuronal subtype specification has relevance to human heath. My lab and others have identified numerous key fate determinants involved in specifying distinct photoreceptor neuron subtypes, using the genetically amenable Drosophila eye as a model system. Recently, we showed that four conserved transcription factors - [Otd (OTX/CRX in vertebrates), Tj (MAF/NRL), Senseless (GFI1), and Pph13 (ARX)] - play crucial roles in binary fate choices between blue and green photoreceptors (PRs). Moreover, we demonstrated that these PR fate determinants differentially regulate the expression and/or activity of two key components of the Hippo tumor suppressor pathway - Wts and Yki - to control cell type-specific gene expression in blue vs green PRs. While the Hippo pathway is well known for its role in growth control, our study revealed novel mechanistic insights into how the Hippo pathway controls cell fate specification in postmitotic cells. Here, we propose experiments to expand our knowledge on how the Hippo pathway controls cell fate specification, testing the central hypothesis that cross-talk between PR fate determinants and Hippo pathway mediators is critical for precise binary cell fate choices between blue and green PRs. Using genetic, biochemical and molecular approaches, we propose to define key crosstalk nodes between the PR fate determinants and the Hippo pathway and elucidate their underlying molecular mechanisms. These nodes include a) differential actions of the Hippo pathway effector Sd in blue vs green PRs (Aim 1);b) regulation of the Hippo pathway regulators - melt and wts - in blue and green PRs (Aim 2);and c) crosstalk between Hippo and Smad-dependent signaling to ensure a binary fate decision (Aim 3). Outcomes of this study will serve as an important guide for future studies on the role of the Hippo pathway in PR specification in other organisms, and for neuronal specification in general.
Understanding how distinct neuron types are formed and maintained in the nervous system is essential for combatting numerous neurological disorders. This study reveals new mechanisms of how distinct neuronal populations arise, which involves a complex integration of factors previously associated with neurodegeneration and cancer. Thus, the completion of these studies will serve as a framework for developing therapies for neurological diseases and cancer.
|Friedrich, Markus; Cook, Tiffany; Zelhof, Andrew C (2016) Ancient default activators of terminal photoreceptor differentiation in the pancrustacean compound eye: the homeodomain transcription factors Otd and Pph13. Curr Opin Insect Sci 13:33-42|
|Cook, Tiffany A (2015) Hypo- or hyper-hippo: a balancing act with bHLH transcription factors. Dev Cell 32:133-5|