The mammalian forebrain, with its components the basal ganglia (subpallium) and cortex (pallium), is a result of advanced evolutionary processes. Although several genetic pathways that establish cell diversity within the developing telencephalon have been identified, only a few factors have been shown to control the earliest steps of anteroposterior (A/P) and dorsoventral (D/V) patterning [1].
From embryonic stage E7.5 onwards, the telencephalic vesicles are progressively regionalized through complex interactions of secreted ligands from inductive centers, and by the regionalized or graded expression of transcription factors [1-3]. FGF (Fibroblast Growth Factor) signaling acts downstream of SHH (Sonic Hedgehog) and is required to both specify and promote the proliferation and/or survival of ventral cell types in the telencephalon [4-7], while WNT (Wint) signaling apparently elaborates archicortical morphogenesis [8,9]. Interestingly, modulation of the normal expression gradient of Fgf8 in the early cortical primordium alters the molecular location and the size of cortical domains along the A/P axis [10,11]. At the beginning of cortical neurogenesis, several transcription factors display graded expression in cortical progenitors along the main axes, which seems to confer cortical regional specificity [1-3]. The transcription factors Emx2 and Pax6 exhibit an opposing expression gradient along the A/P axis of the forebrain. Accordingly, single mutants of either Emx2 or Pax6 show a severe shrinkage of the corresponding cortical area, which normally expresses these genes at high levels [2]. Of note, Emx2 is the only factor that has been shown to additionally affect the innervation of thalamic axons into the cortex [1-3].
The zinc-finger transcription factor Sp8 is expressed in the developing nervous system, limbs and the tail bud. Analysis of Sp8 knockout mice revealed severe truncations of the limbs and tail, while at the midbrain-hindbrain boundary (MHB) a defect of A/P patterning occurred (12, 13, 14). Interestingly, Fgf8 expression is affected in both cases, suggesting that Sp8 may be required for the maintenance of Fgf8 activity in these tissues. Recent evidence indicates that abolishment of Sp8 function (in the ventral telencephalon) provokes enhanced apoptosis in progenitors of the dorsal lateral ganglionic eminence (dLGE), causing the loss of specific olfactory bulb interneurons [15]. Additionally, Sp8 displays a graded expression pattern in cortical progenitors, with highest expression in the medial pallium.
To gain more insights into the role of Sp8 in the developing telencephalon, we created Foxg1-Cre-mediated conditional Sp8 mutants. We present evidence that, in the absence of Sp8, while Shh signaling is normal, the D/V patterning at the medial telencephalic wall is perturbed. Midline derivatives of the subpallium are malformed or completely missing. Additionally, due to the modulation of the graded expression territories of Emx2 and Pax6 in pallial progenitors, a caudalization of cortical areas occurs. Our study indicates that Sp8 function is required to prevent pallial progenitors from apoptosis, and to control the molecular specification of subsets of cortical layer neurons. This is consistent with an essential role for Sp8 in the patterning of the developing forebrain along the A/P and D/V axes. Furthermore, our findings support the idea of a direct interaction between Sp8 and Emx2 proteins.
Answers to all your Biology Questions
