| Summary: | <p>Abstract</p> <p>Telencephalic patterning centers, defined by the discrete expression domains of distinct morphogens, <it>Fgf</it>s in the commissural plate (CoP), <it>Wnt</it>s and <it>Bmp</it>s in the cortical hem, and a ventral domain of Sonic hedgehog (<it>Shh</it>), are postulated to establish during development the initial patterning of the telencepahlon, including the neocortex. We show that the expression patterns of <it>Sp5</it>, <it>Sp8</it>, and <it>Sp9</it>, members of the <it>Sp8</it>-like family that are homologues of <it>Drosophila buttonhead</it>, correlate during early embryonic development with these three telencephalic patterning centers. To study potential functional relationships, we focused on <it>Sp8</it>, because it is transiently expressed in the CoP coincident with the expression of <it>Fgf8</it>, a morphogen implicated in area patterning of the neocortex. We also show that <it>Sp8 </it>is expressed in cortical progenitors in a high to low anterior-medial to posterior-lateral gradient across the ventricular zone. We used <it>in utero </it>electroporation of full-length and chimeric expression constructs to perform gain-of-function and loss-of-function studies of interactions between <it>Sp8 </it>and <it>Fgf8 </it>and their roles in cortical area patterning. We show that <it>Fgf8 </it>and <it>Sp8 </it>exhibit reciprocal induction <it>in vivo </it>in the embryonic telencephalon. <it>Sp8 </it>also induces downstream targets of <it>Fgf8</it>, including ETS transcription factors. <it>In vitro </it>assays show that Sp8 binds <it>Fgf8 </it>regulatory elements and is a direct transcriptional activator of <it>Fgf8</it>. We also show that Sp8 induction of <it>Fgf8 </it>is repressed by Emx2 <it>in vitro</it>, suggesting a mechanism to limit <it>Fgf8 </it>expression to the CoP. <it>In vivo </it>expression of a dominant negative <it>Sp8 </it>in the CoP indicates that <it>Sp8 </it>maintains expression of <it>Fgf8 </it>and also its effect on area patterning. Ectopic expression of Sp8 in anterior or posterior cortical poles induces significant anterior or posterior shifts in area patterning, respectively, paralleled by changes in expression of gene markers of positional identity. These effects of <it>Sp8 </it>on area patterning oppose those induced by ectopic expression of <it>Fgf8</it>, suggesting that in parallel to regulating <it>Fgf8 </it>expression, <it>Sp8 </it>also activates a distinct signaling pathway for cortical area patterning. In summary, <it>Sp8 </it>and <it>Fgf8 </it>robustly induce one another, and may act to balance the anterior-posterior area patterning of the cortex.</p>
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