A Retinoic Acid Autoregulatory Loop Governing Prefrontal-Motor Arealization

Abstract

The frontal lobe comprises the prefrontal association cortex (PFC), which supports complex cognition and goal-directed behavior, and the motor cortex (MC), which executes movement. A hallmark of primate brain evolution is PFC expansion accompanied by a posterior displacement of the MC. Retinoic acid (RA) signaling has emerged as a key regulator of PFC specification and expansion. However, the mechanisms that spatially confine RA signaling within the developing PFC, and the downstream RA-responsive gene networks, remain poorly understood. Here we defined an RA-associated gene regulatory network (RA-GRN) in the developing human PFC and identified MEIS2, which encodes a transcription factor linked to intellectual disability and autism spectrum disorder (ASD), as its key hub of this network. Conditional deletion of Meis2 in postmitotic cortical excitatory neurons in mice results in a partial respecification of prospective prefrontal association territories toward motor-like molecular and connectional features, highlighting a critical role of postmitotic neurons in establishing and maintaining cortical areal identities. Concomitant with Meis2 loss, the population of excitatory neurons expressing the RA-synthesizing enzyme ALDH1A3, and consequently RA signaling itself, is markedly reduced in the developing medial prefrontal cortex (mPFC). These findings revealed a conserved autoregulatory loop: RA [->] MEIS2 [->] ALDH1A3 [->] RA that reinforces a PFC-enriched RA gradient and organizes the MC-PFC axis. Together, our findings reveal a postmitotic mechanism by which specific features of neuronal identity reinforce RA signaling to define key features of prefrontal and motor cortical territories, linking a classic morphogen to transcriptional identity, neural circuit formation and function, and potentially to psychiatric disorders.