Genetics of patterning in the zebrafish neural plate. The goal of this project is to identify genetic and molecular mechanisms that ensure the correct type and number of primary neurons are generated during early development of the zebrafish neural plate. In vertebrates, signals that determine position of primary neurons are supposed to derive from axial mesoderm and floorplate (motoneurons), and ectoderm and roof plate (sensory neurons). Combinatorial signaling of anterioposterior and dorsoventral patterning genes determine what type of neurons form along the rostrocaudal axis of the CNS. In analogy to drosophila, neurogenic genes have been suggested to be involved in control of neuronal number. While such a scaffold of interaction is supported by significant experimental evidence, the precise nature of the genetic control of these patterning events is unknown. Previous screens in the laboratory have identified mutations which delete subpopulations of primary neurons (in bozozok primary motoneurons are not formed); or affect the shape of the neural plate and position and number of primary neurons (in trilobite and knypek the neural plate is wider and shorter; fewer primary motoneurons form, and sensory neurons are spread over an unusually large area); or control the number of primary neurons (mind bomb is a neurogenic mutant and forms supernumerary primary neurons). These and other mutations have established zebrafish as a powerful genetic system to study vertebrate CNS patterning. 1. Analysis of mutations affecting specification of primary neurons. We will characterize the neurogenic phenotype of mind bomb with respect to specific neuronal subtypes associated with supernumerary neurons and examine changes n the expression of identified zebrafish homologues of proneural and neurogenic genes. In trilobite and knypek, we will study changes in proneural field size and neuronal number. 2. A genetic screen will be carried out to specifically identify genes controlling number and distribution of primary neurons. Neuronal specific markers will be used to identify specific phenotypes. The previous screens were based on visual inspection of embryos only, and would have missed many neuron specific mutations. 3. Genetic mapping of existing and new mutations as well as candidate genes. Mapping of mutations and of candidate cloned cDNAs on the zebrafish genetic map will reveal potential candidate genes and prepare for molecular analysis of the mutant loci. Results from the proposed study will improve understanding of motoneuronal development, and may provide new paradigms to develop novel treatments for paralyzed states and neurodegeneration.
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