Analysis of Fgf17 roles and regulation in mammalian forebrain development

University Of California, San Francisco, San Francisco CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Fgf17, one of four Fgfs expressed in the vertebrate rostral forebrain signaling center (RFSC), is required for normal regionalization of the dorsal frontal cortex. Postnatal Fgf17-/- mice exhibit cortical patterning defects, as well as behavior and cognition phenotypes that mirror aspects of the clinical presentation of autism spectrum disorders. The specific roles of Fgf17 during brain development and their effects on postnatal brain functions are not yet known. The proposed studies use mouse genetics to analyze the roles and regulation of Fgf17 in the RFSC, striving toward three long-term goals: (1) determine how temporally and spatially distinct Fgf functions impact brain development and function; (2) understand functional specificity of Fgfs in the RFSC; and (3) determine how extrinsic and intrinsic cues coordinately regulate forebrain development and impact cognition and behavior. Aim 1 uses conditional Fgf 17 knockout mice and an inducible Cre line to identify critical periods of Fgf 17 signaling for regional forebrain development, and then to define Fgf 17 roles during this/these period/s. Specific Aim 2 uses Cre-mediated lineage tracing to fate map Fgf8- versus Fgf17-expressing RFSC cells, and to determine whether Fgf17 is required for the development of these lineages. In addition to providing fate information, this may reveal targets of RFSC Fgf 17 signaling and/or developmental mechanisms underlying functional differences between Fgf8 and Fgf17 in this context. Finally, Aim 3 addresses mechanisms of Fgf 17 regulation in the RFSC using two novel forebrain enhancers of Fgf 17. Transgenic mice will be used to identify developmental contexts in which the enhancers drive expression during development. Then, enhancer regions and putative transcription factor binding sites that are essential for the enhancers' regulatory activities will be identified in vitro. These experiments aim to identify transcription factors and/or signaling pathways that regulate RFSC Fgf 17 expression, and thereby elucidate how RFSC functions are integrated with concurrent molecular events in the developing forebrain. Fgf17null phenotypes suggest that factors that regulate Fgf17 in the RFSC may also impact postnatal cognition and behavior. This work will provide novel insight as to the molecular mechanisms of Fgf17 function and regulation in forebrain development. It will also lay the foundation for future collaborative projects (beyond the scope of this proposal) that will determine which roles of Fgf17 underlie the cognitive and behavioral phenotypes of Fgf17null mice. Together, these analyses will help to identify developmental processes and regulatory factors that contribute to the etiologies of autism and related psychiatric disorders. [unreadable] [unreadable]