Lineage & Development of the Midbrain & Hindbrain

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DESCRIPTION (provided by applicant): The vertebrate brain is derived from the rostral neural tube, which first appears as a series of morphological constrictions termed neuromeres that delineate the major subdivisions of the brain. Tissue specific patterning of neuromeres results in highly specialized anatomical and functional units in the adult. One method to accomplish these remarkable developmental events is with a combinatorial mechanism of patterning that involves the formation of a lineage restriction boundary concomitant with the emergence of an 'organizer' that instructs specific positional information and fates on adjacent tissue. This mechanism has been shown to pattern Drosophila wing imaginal disks as well as chick and mouse limb but not as of yet brain. The mesencephalon (mes) and metencephalon (met) are opposed to each other and are clearly distinct morphological structures. During early development the mes, which expresses Otx2 and Wnt1, and the met, which expresses Gbx2 and Fgf8, are juxtaposed at a well-defined constriction along the anteroposterior axis defined as the isthmus. The differentially expressed mes/met genes specify regional identity and potentially segregate two populations of cells into presumptive compartments. Interestingly, the isthmus has been shown to be an organizer using classical transplantation studies and appears to mediate instructional events through a complex genetic cascade initiated by the morphogen Fgf8. The secreted factor Wnt1 may play a role in maintaining mes/met boundary integrity, though this mechanism has not been closely studied. This proposal will investigate whether the mes/met juxtaposition is a lineage restriction boundary and addresses the role of Wnt1 in mes/met boundary formation or maintenance. I propose to address these questions by genetically marking and fate mapping Wnt1 expressing cells of the mes and Gbx2-expressing cells of the met using two inducible Cre/loxP systems. To address whether Wnt1 plays a role in establishing and/or maintaining the mes/met interface, I will generate a conditional Wnt1 mutant allele and assess the phenotypic consequences of loss of Wnt1 function at different developmental stages.