Zbtb20 may regulate the postnatal maturation of parvalbumin interneurons

Abstract

The onset of expression of the transcription factor (TF) Nkx2.1 at the ninth embryonic day signals the start of subdivision of the mouse forebrain into its two progenitor zones: the pallium and the subpallium. The pallium being the origin of the cortical excitatory neurons and the subpallium, comprising four progenitor domains: tree ganglionic eminences (GE) known as Lateral, Medial and Caudal GE, respectively (LGE, MGE, CGE) and a small region named the preoptic area, giving rise to almost all cortical and striatal interneurons (IN). MGE, gives rise to 60% of all cortical IN, namely parvalbumin (PV) and somatostatin positive INs, and thus was the first zone we investigated. Of all subpallial progenitor zones the LGE does not contribute to neocortical neurogenesis, but gen­erates neurons only to the olfactory bulb and striatum. Zbtb20 is a zinc finger BTB domain-containing TF related to normal development of the mammalian forebrain with mutant mice having severe defects in the formation of the hippocampus and the normal formation of the neocortical layers due to problems during the neurogenesis of the pallial glutamatergic neurons. The strong expression of this TF in the GE poses the question of its role in cor­tical IN development. In order to address this problem we employed a loss-of-function strategy by means of Zbt­b20lacZ/lacZ knock-out mouse line. We have already demonstrated almost complete absence of PV INs in the neo­cortex at postnatal day (P)12. We then wanted to explore the PV levels at later stages and were able to do so only at stage P15 due to early postnatal mortality of the homozygous mutants. We then found a more substantial number of PV+ INs compared to P12, but severe reduction was still present. We analyzed the levels of PV+ INs in the WT and heterozygous Zbtb20lacZ/+ mice at P28 and found a substantial reduction on the heterozygous mutants. The data so far hints both at the possibility that the phenotype seen for PV+ INs can be in part due to delayed postna­tal maturation and in part to a dose-dependent effect of Zbtb20 on PV+ IN generation.