Nr4a2, A Key Factor Controlling the Development and Functional Maintenance of Forebrain Car3 Neurons
Yun‑Chao Tao1 · Li Zhao1 · Qiong Zhang2 · Xi‑Yue Liu1 · Wei‑Tang Liu3 · Ze‑Xuan Li2 · Ling Hu2 · Lei Zhang4,5 · Jia‑Yin Chen2 · Yu‑Qiang Ding1,2,3,6 · Ning‑Ning Song2
1 State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai 200032, China
2 Laboratory Animal Center, Fudan University, Shanghai 200032, China
3 Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, Shanghai 200032, China
4 Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), Tongji University School of Medicine, Shanghai 201619, China
5 Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai 200092, China
6 Huashan Institute of Medicine (HS‑IOM), Huashan Hospital, Fudan University, Shanghai 200040, China
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.
Keywords
Nr4a2; Car3; Development; Function maintenance; Anxiety
