Prox1Regulates the Subtype-Specific Development of Caudal Ganglionic Eminence-Derived GABAergic Cortical Interneurons

Abstract

Neurogliaform (RELNϩ) and bipolar (VIPϩ) GABAergic interneurons of the mammalian cerebral cortex provide critical inhibition locally within the superficial layers. While these subtypes are known to originate from the embryonic caudal ganglionic eminence (CGE), the specific genetic programs that direct their positioning, maturation, and integration into the cortical network have not been elucidated. Here, we report that in mice expression of the transcription factor Prox1 is selectively maintained in postmitotic CGE-derived cortical interneuron precursors and that loss of Prox1 impairs the integration of these cells into superficial layers. Moreover, Prox1 differentially regulates the postnatal maturation of each specific subtype originating from the CGE (RELN, Calb2/VIP, and VIP). Interestingly, Prox1 promotes the maturation of CGE-derived interneuron subtypes through intrinsic differentiation programs that operate in tandem with extrinsically driven neuronal activity-dependent pathways. Thus Prox1 represents the first identified transcription factor specifically required for the embryonic and postnatal acquisition of CGE-derived cortical interneuron properties.

Evidence That the Laminar Fate of LGE/CGE-Derived Neocortical Interneurons Is Dependent on Their Progenitor Domains

“…LGE/CGE-derived interneurons express several neurochemical markers including VIP, RLN, NPY, and calretinin (Lee et al, 2010;Ma et al, 2012;Miyoshi et al, 2015). These molecules are expressed across all cortical layers.…”

“…Neocortical interneurons were originally thought to be derived from the LGE based on a genetic study (Anderson et al, 1997) and tracing studies using rat embryos injected with lipophilic dyes (de Carlos et al, 1996;Tamamaki et al, 1997). The interpretation of these results came into question with the findings that the MGE is an origin for interneurons (Lavdas et al, 1999;Sussel et al, 1999;Wichterle et al, 1999), that MGE-derived interneurons migrate through the LGE (Anderson et al, 2001;Wichterle et al, 2001), and that in vivo transplantation studies failed to show a LGE origin of cortical interneurons (Wichterle et al, 2001;Nery et al, 2002). Nevertheless, there are several lines of evidence consistent with the notion that the LGE gives rise to some cortical interneurons.…”

“…The caudal ganglionic eminence (CGE) is the second largest source of neocortical interneurons (for review, see Gelman and Marín, 2010;Rudy et al, 2011), although the preoptic area (POA) also generates a small number of interneurons (Nery et al, 2002;Gelman et al, 2009). Like the MGE, the CGE generates neurochemically, morphologically, and electrophysiologically diverse types of interneurons (Lee et al, 2010;Vucurovic et al, 2010).…”

“…Like the MGE, the CGE generates neurochemically, morphologically, and electrophysiologically diverse types of interneurons (Lee et al, 2010;Vucurovic et al, 2010). For example, there are subsets of interneurons that express vasoactive intestinal peptide (VIP), reelin (RLN), calretinin, neuropeptide Y (NPY), or their combination (Lee et al, 2010;Rubin et al, 2010;Ma et al, 2012;Miyoshi et al, 2015). Some interneurons extend radially oriented processes, whereas others show multipolar shape and neurogliaform morphology (Hajó s et al, 1988;Kawaguchi and Kubota, 1996;Lee et al, 2010;.…”

Molecular control of two novel migratory paths for CGE-derived interneurons in the developing mouse brain

“…5HT3aR is expressed in migrating and mature CGE-and POA-derived cells (Lee et al, 2010;Vucurovic et al, 2010) and is cell-autonomously required for the migration and positioning of RLN + INs in the neocortex (Murthy et al, 2014). Finally, SP8 and PROX1 are transcription factors expressed principally in subpopulations of lateral ganglionic eminence (LGE)/CGE-derived cortical INs (Ma et al, 2012;Rubin and Kessaris, 2013;Rudy et al, 2011) and a recent report has demonstrated a crucial role for PROX1 in the embryonic and postnatal acquisition of CGE-derived cortical IN properties (Miyoshi et al, 2015).…”