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Pyk2 suppresses contextual fear memory in an autophosphorylation-independent manner
Jin Zheng1,2,† , Lun Suo1,3,†,* , Yuxiao Zhou1,2,† , Liling Jia1,2,† , Jingwei Li1,2 , Yanping Kuang3 , Donghong Cui4 , Xuehong Zhang1 , Qiang Wu1,2,*
1Center for Comparative Biomedicine, Ministry of Education Key Lab of Systems Biomedicine, State Key Laboratory of Oncogenes and Related Genes, Joint International Research Laboratory of Metabolic and Developmental Sciences, Institute of Systems Biomedicine, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
2WLA Laboratories, Shanghai, China
3Department of Assisted Reproduction, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
4Shanghai Mental Health Center, Shanghai Key Laboratory of Psychotic Disorders, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
These authors contributed equally to this work
*Correspondence to:Lun Suo , Qiang Wu ,
J Mol Cell Biol, Volume 13, Issue 11, November 2021, 808-821,
Keyword: Pyk2 cell adhesion kinase, protocadherin, genetics, spine dynamics, fear memory

Clustered protocadherins (Pcdhs) are a large family of cadherin-like cell adhesion proteins that are central for neurite self-avoidance and neuronal connectivity in the brain. Their downstream nonreceptor tyrosine kinase Pyk2 (proline-rich tyrosine kinase 2, also known as Ptk2b, Cakb, Raftk, Fak2, and Cadtk) is predominantly expressed in the hippocampus. We constructed Pyk2-null mouse lines and found that these mutant mice showed enhancement in contextual fear memory, without significant change in auditory-cued and spatial-referenced learning and memory. In addition, by preparing Y402F mutant mice, we observed that Pyk2 suppressed contextual fear memory in an autophosphorylation-independent manner. Moreover, using high-throughput RNA sequencing, we found that immediate early genes, such as Npas4, cFos, Zif268/Egr1, Arc, and Nr4a1, were enhanced in Pyk2-null mice. We further showed that Pyk2 disruption affected pyramidal neuronal complexity and spine dynamics. Thus, we demonstrated that Pyk2 is a novel fear memory suppressor molecule and Pyk2-null mice provide a model for understanding fear-related disorders. These findings have interesting implications regarding dysregulation of the Pcdh‒Pyk2 axis in neuropsychiatric disorders.