Center 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.
WLA Laboratories, Shanghai, China.
J Mol Cell Biol. 2022 Jan 21;13(11):808-821. doi: 10.1093/jmcb/mjab057.
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.
聚类原钙黏蛋白（Pcdhs）是一大类钙黏蛋白样细胞黏附蛋白家族，对于脑内轴突的自我回避和神经元的连接至关重要。其下游非受体酪氨酸激酶 Pyk2（富含脯氨酸的酪氨酸激酶 2，也称为 Ptk2b、Cakb、Raftk、 Fak2 和 Cadtk）主要在海马体中表达。我们构建了 Pyk2 敲除小鼠品系，发现这些突变小鼠的情景恐惧记忆增强，而听觉提示和空间参照学习和记忆没有明显变化。此外，通过制备 Y402F 突变小鼠，我们观察到 Pyk2 以非自身磷酸化依赖的方式抑制情景恐惧记忆。此外，通过高通量 RNA 测序，我们发现即时早期基因，如 Npas4、cFos、Zif268/Egr1、Arc 和 Nr4a1，在 Pyk2 敲除小鼠中增强。我们进一步表明，Pyk2 缺失会影响锥体神经元的复杂性和棘突动力学。因此，我们证明了 Pyk2 是一种新型的恐惧记忆抑制分子，Pyk2 敲除小鼠为理解与恐惧相关的疾病提供了模型。这些发现对于神经精神疾病中 Pcdh-Pyk2 轴的失调具有有趣的意义。
