Sp8 exhibits reciprocal induction with Fgf8 but has an opposing effect on anterior-posterior cortical area patterning

Many homeotic genes originally identified in Drosophila have important roles in vertebrate development. Buttonhead (btd), empty spiracles (ems), and orthodenticles (otd) were identified through mutagenesis screens as genes required for anterior head development in Drosophila [1-3]. Vertebrate homologues of ems and otd, which encode the Emx and Otx families of transcription factors (TFs), respectively, have been studied extensively, particularly their roles in mammalian forebrain development [4,5]. Vertebrate homologues of btd, a member of the Sp1-Zn finger family of TFs, have also been identified [6-8], but in contrast to homologues of ems and otd, they have been studied relatively little, particularly their roles in brain development.Nine genes have been identified in mammals as btd homologues and the proteins they encode share btd and Zn finger domains. Based on the domain structures of their protein products, these nine genes are divided into a Sp1-like family (Sp1-4) and a Sp8-like family (Sp5–9). However, because Sp8 can rescue the defects in head development in Drosophila btd mutants, whereas Sp1 cannot [9], Sp8 and its family are viewed as the functional homologues of Drosophila btd. Mice deficient for either Sp5 or Sp8 have been reported. Sp5 knockout mice reportedly have no overt phenotypes [10]. In contrast, analyses of Sp8 knockout mice [9,11], complemented by retrovirus-mediated overexpression studies in embryonic chicks using dominant negative and active forms of Sp8 [8], indicate that Sp8 is required for limb and head formation.A prominent role for Sp8 in limb development is to maintain the expression of several morphogens, including fibroblast growth factor (Fgf)8, bone morphogenic protein (Bmp)4, and Sonic hedgehog (Shh) [9,11]. Because these morphogens have prominent roles in forebrain development, we examined the expression of the Sp8-like family members in the developing mouse forebrain to determine their potential for roles in forebrain patternin