An evolutionarily acquired microRNA shapes development of mammalian cortical projections

Abstract

The corticospinal tract is unique to mammals and the corpus callosum is unique to placental mammals (eutherians). The emergence of these structures is thought to underpin the evolutionary acquisition of complex motor and cognitive skills. Corticospinal motor neurons (CSMN) and callosal projection neurons (CPN) are the archetypal projection neurons of the corticospinal tract and corpus callosum, respectively. Although a number of conserved transcriptional regulators of CSMN and CPN development have been identified in vertebrates, none are unique to mammals and most are coexpressed across multiple projection neuron subtypes. Here, we discover 17 CSMN-enriched microRNAs (miRNAs), 15 of which map to a single genomic cluster that is exclusive to eutherians. One of these, miR-409-3p, promotes CSMN subtype identity in part via repression of LMO4, a key transcriptional regulator of CPN development. In vivo, miR-409-3p is sufficient to convert deep-layer CPN into CSMN. This is a demonstration of an evolutionarily acquired miRNA in eutherians that refines cortical projection neuron subtype development. Our findings implicate miRNAs in the eutherians’ increase in neuronal subtype and projection diversity, the anatomic underpinnings of their complex behavior.

MiR-137 and miR-122, two outer subventricular zone-enriched non-coding RNAs, regulate basal progenitor expansion and neuronal differentiation

“…Non-coding RNAs and, especially, microRNAs are particularly interesting candidates in this respect as their numbers increase with evolution (Liu et al, 2013). Non-coding RNAs fine-tune various aspects of neurogenesis across species, allowing BP amplification in the oSVZ and, secondarily, cortical expansion, in particular through formation of gyri (Martinez-Martinez et al, 2016, Nowakowski et al, 2018, Arcila et al, 2014, Ayoub et al, 2011, Fietz at al., 2012, de Juan Romero et al, 2015, Diaz et al, 2020. Supporting a role for microRNAs in cortical expansion, here we show that overexpression of the ferret and human oSVZ-enriched microRNAs miR-137 and miR-122 in the mouse neocortex, which is normally devoid of these microRNAs, leads to increased BP self-replication and slowing down of neuronal differentiation pace, respectively.…”

MicroRNAs Instruct and Maintain Cell Type Diversity in the Nervous System

“…miR-409-3p suppresses CPN fate in favor of CSMN development by downregulating LMO4, a transcription factor known to promote CPN areal identity. Layer V CSMN and CPN are born from the same progenitors and initially all express LMO4, so miR-409-3p is thought to mediate divergence of these two cell types ( Diaz et al, 2020 ). Meanwhile, cortical inhibitory interneurons are born in several progenitor zones distant from the cortex and specify into different subtypes depending on which progenitor population they derived from.…”

“…miR-409-3p promotes specification of CSMN fate over other projection neuron fates, and this includes the specific axon targeting of CSMNs. Overexpression of miR-409-3p caused more cells to not only express CSMN markers, but also to extend axons to the internal capsule, functionally joining the corticospinal tract ( Diaz et al, 2020 ).…”

miR-137 and miR-122, two outer subventricular zone non-coding RNAs, regulate basal progenitor expansion and neuronal differentiation

“…Non-coding RNAs and especially microRNAs are particularly interesting candidates in this respect because their numbers increase with evolution ( Liu et al., 2013 ). Non-coding RNAs fine-tune various aspects of neurogenesis, allowing BP amplification in the oSVZ and, secondarily, cortical expansion, in particular via gyrus formation ( Martinez-Martinez et al., 2016 ; Nowakowski et al., 2018 ; Arcila et al., 2014 ; Ayoub et al., 2011 ; Fietz et al., 2012 ; De Juan Romero et al., 2015 ; Diaz et al., 2020 ). Here we show that, upon overexpression of the ferret and human oSVZ-expressed microRNAs miR-137 and miR-122 in the mouse neocortex (which is normally devoid of these microRNAs), miR-137 acts to increase proliferative divisions in BPs, ultimately resulting in increased superficial layer neuron production, whereas miR-122 acts in newborn neurons to slow their differentiation pace, potentially allowing longer distances to be covered before differentiation occurs.…”