Shh maintains NkK2.1 in the MGE by a Gli3-independent mechanism

gamma-Aminobutyric acidergic (GABAergic) interneurons perform crucial roles in cortical development and function. These roles are executed by diverse subgroups of interneurons, and dysfunction of particular subgroups may contribute to a variety of neuropsychiatric diseases. In rodents, most cortical interneurons originate in the pallidal telencephalon that also gives rise to the GABAergic neurons of the striatum and other ventral structures. In this paper, we examine the evidence for distinct origins of interneuron subgroups and then discuss the role of the homeobox gene thyroid transcription factor1 (Ttf-1 or Nkx2.1) in the specification of interneurons from the medial ganglionic eminence (MGE). Nkx2.1 is induced in the pallidal telencephalon by the action of sonic hedgehog (Shh) that antagonizes formation of the dorsalizing Gli3 repressor (Gli3R) protein. Recent evidence suggests that Shh is also required to maintain Nkx2.1 expression, and thus MGE interneuron specification, during embryonic neurogenesis. Here we provide evidence that, in contrast to the initial induction of Nkx2.1 during telencephalic patterning, the Nkx2.1 maintenance function of Shh does not require blocking the formation of the Gli3R. The plastic nature of Nkx2.1 expression during the age range of interneuron genesis suggests that factors regulating this gene can be critical determinants of the balance of excitation and inhibition in the postnatal cerebral cortex.