Clustered protocadherins(Pcdhs)are a large family of cadherin-like cell adhesion proteins that are central for neurite selfavoidance and neuronal connectivity in the brain.Their downstream nonreceptor tyrosine kinase ...Clustered protocadherins(Pcdhs)are a large family of cadherin-like cell adhesion proteins that are central for neurite selfavoidance 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 fearrelated disorders.These findings have interesting implications regarding dysregulation of the Pcdh–Pyk2 axis in neuropsychiatric disorders.展开更多
基金supported by grants from the National Natural Science Foundation of China(31200825 to L.S.and 31630039 to Q.W.)the Ministry of Science and Technology of China(2017YFA0504203 and 2018YFC1004504)+2 种基金the Science and Technology Commission of Shanghai Municipality(19JC1412500 and 21DZ2210200 to Q.W.)Shanghai Jiao Tong University Scientific and Technological Innovation Funds(17JCYB12 to L.S.)Q.W.is a Shanghai Subject Chief Scientist.
文摘Clustered protocadherins(Pcdhs)are a large family of cadherin-like cell adhesion proteins that are central for neurite selfavoidance 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 fearrelated disorders.These findings have interesting implications regarding dysregulation of the Pcdh–Pyk2 axis in neuropsychiatric disorders.
