Postmitotic Nkx2-1 Controls the Migration of Telencephalic Interneurons by Direct Repression of Guidance Receptors

Abstract

Summary The homeodomain transcription factor Nkx2-1 plays key roles in the developing telencephalon, where it regulates the identity of progenitor cells in the medial ganglionic eminence (MGE) and mediates the specification of several classes of GABAergic and cholinergic neurons. Here we have investigated the postmitotic function of Nkx2-1 in the migration of interneurons originating in the MGE. Experimental manipulations and mouse genetics show that downregulation of Nkx2-1 expression in postmitotic cells is necessary for the migration of interneurons to the cortex, whereas maintenance of Nkx2-1 expression is required for interneuron migration to the striatum. Nkx2-1 exerts this role in the migration of MGE-derived interneurons by directly regulating the expression of a guidance receptor, Neuropilin-2, which enables interneurons to invade the developing striatum. Our results demonstrate a novel role for the cell-fate determinant Nkx2-1 in regulating neuronal migration by direct transcriptional regulation of guidance receptors in postmitotic cells.

Origin and Molecular Specification of Globus Pallidus Neurons

“…We have shown previously that Nkx2-1 is expressed in virtually all progenitor cells in the MGE and the POA, as well as in postmitotic cells that populate the GP and other subpallial structures (Sussel et al, 1999;Marín et al, 2000;Flames et al, 2007;Nó brega-Pereira et al, 2008). Analysis of the expression of Nkx2-1 in the adult GP revealed that virtually all PV-positive (PV ϩ ) neurons also contain this transcription factor ( Fig.…”

Loss of COUP-TFI Alters the Balance between Caudal Ganglionic Eminence- and Medial Ganglionic Eminence-Derived Cortical Interneurons and Results in Resistance to Epilepsy

“…known to determine the identity of progenitor cells in the MGE (Sussel et al, 1999;Butt et al, 2008;Nó brega-Pereira et al, 2008), and its downstream target Lhx6 , which starts to be expressed as soon as MGE-derived progenitors leave the VZ (Liodis et al, 2007). No obvious changes in the expression pattern of Nkx2.1 and Lhx6 at rostromedial and caudal levels were observed in E13.5 COUP-TFI CKO-Dlx5/6 embryos (Fig.…”

Guiding Neuronal Cell Migrations

“…For instance, interneurons are prevented from migrating in ventral direction by a so far unidentified chemorepellent activity present in the preoptic area Wichterle et al 2003). MGE-derived cortical interneurons also avoid the developing striatum in response to class III semaphorins (Sema3A and Sema3F) expressed in this structure Nó brega-Pereira et al 2008). This mechanism involves Nrp1 and Nrp2, the receptors for Sema3A and Sema3F, respectively.…”