Project Summary Mutations in chromatin regulators have emerged as a major cause of Neurodevelopmental disorders, such as autism spectrum disorders, schizophrenia, and intellectual disabilities. Following the gene discoveries, many mouse models and human cells resembling these genetic lesions have been made and characterized. These chromatin-linked Neurodevelopmental disorders models often display misregulation of genes with relevant brain functions, including synaptic plasticity. Most work has focused on such brain-associated genes to explain the cellular and behavioral phenotypes. An underappreciated observation is that several Neurodevelopmental disorders models display ectopic expression of germline genes, which should only be expressed in the testis or ovary. No o work thus far has addressed the causal impact of mis-expressed genes on cellular- and behavioral traits. The lack of knowledge prevents us from understanding the mechanisms underlying Neurodevelopmental disorders. If germline gene expression causally impacts neurodevelopment, it would be an ideal drug target because such drugs would not directly interfere with any brain molecules. The overarching goal of this proposal is to address the question—Does ectopic germline gene expression contribute to Neurodevelopmental disorders? Our focus is lysine demethylase 5c (KDM5C), whose loss of function is responsible for a syndromic Neurodevelopmental disorder characterized by intellectual disability, autistic features, and aggressive behavior. As the name suggests, KDM5C reverses H3K4 methylation (H3K4me), a hallmark of transcriptionally-engaged chromatin, and the modification is conserved from yeast to humans. Kdm5c-knockout (KO) mouse model recapitulates the key features of the above behavior seen in human patients. In addition, our unbiased survey of gene misregulation with RNA-seq revealed that the top altered genes were germline-specific genes, derepressed in Kdm5c-KO brain tissues. Furthermore, Stra8 and Dazl, master key genes for germline development, are present in Kdm5c-KO stem cells. These data indicate that Kdm5c deletion led to the soma-to-germline transformation to some extent. The proposed study will test the hypothesis—germline gene expression bestows ‘germcellness’ to the mutant brain and contributes to neurological complications of Kdm5c-KO mice. The proposed study addresses the impact of non-brain genes in Neurodevelopmental disorders models for the first time. Transcriptional silencing of germline genes in somatic cells is proposed to be an essential step for multicellularity, which emerged 1.5 billion years ago. Thus, the proposed study may reveal a deep evolutionary root of several Neurodevelopmental disorders, that can be targeted in future therapeutics.