Cell Fate Specification in the Developing Nervous System

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Proneural transcription factors of the basic helix-loop-helix class have critical, conserved roles in specifying populations of neural precursor cells and in controlling the differentiation of their progeny. Understanding the multiple, qualitatively different functions of these factors is a central goal in developmental neuroscience. The long-term goal of this research is to define at a molecular genetic level the mechanisms by which the C. elegans proneural gene lin-32 controls the generation of three distinct neural cell types from a single neural precursor cell. These three cell types (two neurons called RnA and RnB and a glial-like structural cell, Rnst) together form the ray sensillum, a model sensory organ in the C. elegans male tail. We hypothesize that the progeny of the ray precursor cell are specified combinatorially by a transcriptional cascade that depends both on lin-32 and on the cellular context in which it functions. The research proposed here will identify and functionally characterize the factors that establish this context and those that act to implement specific ray cell fates. Among other characteristics, the genetic sophistication of C. elegans and the ability to observe development and marker gene expression in live animals make the nematode an ideal model for addressing these issues. This proposal outlines three related aims to test our hypothesis by characterizing the regulatory network that coordinates ray development. (1) We will test the novel model that regulated asymmetric lin-32 expression patterns ray cell fates in one branch of the ray sublineage, and explore the role of Wnt/MAPK signaling in this process. (2) We will examine the role of the LIM-HD gene lim-7 in the specification of RnB neuron subtype and determine its relationship to lin-32. (3) We will carry out a novel forward genetic screen and molecularly clone two new genes that act to control neural patterning in the ray sublineage. These studies will define the genetic mechanisms that determine the specificity of proneural gene function and the establishment of neural subtypes in a simple and tractable model. Understanding these mechanisms is essential both for a full appreciation of human neurodevelopmental disease and for the design of rational therapies. Lay summary: Using a small soil roundworm, we will explore the genetic mechanisms that generate cellular complexity in the nervous system. This has special relevance for human diseases in which these processes are disrupted.