# Soma-to-germline Transformation in Neurodevelopmental Disorders?

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $234,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10985566
- **Project number:** 1R21MH135290-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Shigeki Iwase
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $234,000
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10985566

## Citation

> US National Institutes of Health, RePORTER application 10985566, Soma-to-germline Transformation in Neurodevelopmental Disorders? (1R21MH135290-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10985566. Licensed CC0.

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