Fig. 10. Summary of proposed interactions between patterning centers. (A) Postulated signaling cascade downstream of FGF8. Not shown: FOXG1 also represses expression of WNT genes. Dotted lines indicate that the interaction is either indirect or potentially indirect. Note that Foxg1 expression is maintained in part by mTOR (Hentges et al., 1999; Hentges et al., 2001), and that the MAPK cascade blocks BMP signaling through phosphorylation of the linker domain of SMAD (Kretzschmar et al., 1997; Pera et al., 2003). (B) Schema of a frontolateral view of the telencephalon showing the patterning centers as marked by expression of the genes indicated, the cross regulation between the Fgf8 and Bmp4/Wnt3a-expressing centers, and the positive interactions between the Fgf8 and Shh-expressing domains. (C) Postulated pathways interconnecting FGF, BMP, WNT and SHH signaling through the EMX2, FOXG1 and NKX2.1 transcription factors. Note that there is evidence that EMX2 positively regulates BMP/WNT signaling that in turn represses Fgf8 expression (Shinozaki et al., 2004; Muzio et al., 2005; Shimogori et al., 2004). FGF8 signaling is required for induction of Nkx2.1 expression in the telencephalon; we hypothesize that FGF signaling has a general role in ventral neural specification. Not described in this schema is the role that GLI3 plays in regulating the balance between forebrain signaling centers. GLI3 represses SHH-mediated effects on ventralization throughout the nervous system (reviewed by Ruiz et al., 2002). As in more caudal regions of the neural tube, the expression of ventral molecular features expands into dorsal structures within the Gli3 mutant telencephalon (Tole et al., 2000; Rallu et al., 2002). Gli3 mutants exhibit a reduction in BMP and WNT expression at the dorsal midline (Grove et al., 1998; Kuschel et al., 2003) and an expansion of Fgf8 expression (Aoto et al., 2002; Kuschel et al., 2003), leading to the model that GLI3 plays a central role in mediating interactions between the telencephalic signaling centers (Aoto et al., 2002; Kuschel et al., 2003). However, since Shh expression is essentially eliminated from the telencephalon in the Fgf8 mutants, it is not clear whether alterations in Gli3 expression or function might contribute to their phenotypes. CP, commissural plate; Cx, cortex; HT, hypothalamus; LGE, lateral ganglionic eminence; LT, lamina terminalis; M, mesencephalon; MGE, medial ganglionic eminence; OC, optic chiasm; S, septum.