Nr4a2, A Key Factor Controlling the Development and Functional Maintenance of Forebrain Car3 Neurons

Abstract Nr4a2 ( Nurr1 ) is well known to be vital for midbrain dopaminergic neurons. Recent single-cell RNA analyses reveal that Nr4a2 is expressed in lateral cerebral regions, within neurons named L4/L5/L6 IT Car3 . These neurons have attracted intense attention for the molecular mechanisms underlying their development and functions. We classified Car3 neurons into neocortical (Ncx- Car3 ), claustral (CLA- Car3 ), and dorsal endopiriform nucleus (dEn- Car3 ) subpopulations, focusing on the characterization of Ncx- Car3 neurons. These neurons exhibit distinct birthdates and migratory morphologies compared to CLA- and dEn- Car3 neurons, but share a common transcriptomic profile when Nr4a2 is deleted at the embryonic stage or in adulthood. Notably, Nr4a2 misexpression ectopically induces Car3 -enriched genes in vivo . Mice lacking Nr4a2 in Car3 ensembles during the embryonic stage or in adulthood display hyperactivity and reduced anxiety-like behaviors. Therefore, our results demonstrate that Nr4a2 is a key factor in regulating the development and functional maintenance of the forebrain Car3 neurons.