Abstract
Throughout development, neuronal identity is controlled by key transcription factors that determine the unique properties of a cell. During embryogenesis, the transcription factor Prox1 regulates VIP-positive cortical interneuron migration, survival, and connectivity. Here, we explore the role of Prox1 as a regulator of genetic programs that guide the final specification of VIP interneuron subtypes in early postnatal life. Synaptic in vitro electrophysiology in male and female mice shows that postnatal Prox1 removal differentially affects the dynamics of excitatory inputs onto VIP bipolar and multipolar subtypes. RNA sequencing reveals that one of the downstream targets of Prox1 is the postsynaptic protein Elfn1, a constitutive regulator of presynaptic release probability. Further genetic, pharmacological, and electrophysiological experiments demonstrate that removing Prox1 reduces Elfn1 function in VIP multipolar but not in bipolar cells. Finally, overexpression experiments and analysis of native Elfn1 mRNA expression reveal that Elfn1 levels are differentially controlled at the post-transcriptional stage. Thus, in addition to activity-dependent processes that contribute to the developmental trajectory of VIP cells, genetic programs engaged by Prox1 control the final differentiation of multipolar and bipolar subtypes.SIGNIFICANCE STATEMENT The transcription factor Prox1 generates functional diversification of cortical VIP interneuron subtypes in early postnatal life, thus expanding the inhibitory repertoire of the cortex.
Highlights
Cortical interneuron (IN) diversity begins at their place of birth within distinct embryonic progenitor domains (Mi et al, 2018), single-cell sequencing and manipulation experiments at different developmental stages have suggested that INs undergo their final specification while incorporating into the developing circuit (De Marco García et al, 2011; Mayer et al, 2018)
At P4, the eGFP signal was weak, but it increased markedly by P6 (Fig. 1C), indicating an accumulation of eGFP protein within those 2 d. In line with this result, we observed that at P6 most of the bright eGFPexpressing cKO cells show a complete absence of Prox1 signal, while the majority of control cells display Prox1 signal (Fig. 1C). These results show that the removal of Prox1 starts right before P4 and is largely completed by P6
Prenatal removal of Prox1 in embryonic caudal ganglionic eminence-derived cortical INs results in a failure of CR1 VIP INs to migrate to the correct cortical layer, a significant decrease in their numbers, and a subsequent reduction in the excitatory synaptic input onto the remaining cells (Miyoshi et al, 2015)
Summary
Cortical interneuron (IN) diversity begins at their place of birth within distinct embryonic progenitor domains (Mi et al, 2018), single-cell sequencing and manipulation experiments at different developmental stages have suggested that INs undergo their final specification while incorporating into the developing circuit (De Marco García et al, 2011; Mayer et al, 2018). Cortical vasoactive intestinal peptide-expressing (VIP) INs are a diverse population that can be roughly classified into two subgroups: the bipolar and multipolar VIP cells (Bayraktar et al, 1997, 2000; Cauli et al, 2014; Prönneke et al, 2015; Tasic et al, 2018). They make up ,5% of all neurons, VIP INs are critically important for cortical circuit maturation and their malfunction has been implicated in neurodevelopmental disorders
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