# Generation and characterization of a novel mouse line to elucidate CHTF18 function in male and female meiosis

> **NIH NIH R03** · DREXEL UNIVERSITY · 2022 · $74,111

## Abstract

SUMMARY
Chromosome segregation errors are a leading cause of aneuploidy in humans that can have catastrophic clinical
consequences. The fidelity of meiotic chromosome segregation requires well-orchestrated DNA double-strand
break repair. During this critical process, DNA crossovers and the synaptonemal complex tether homologous
chromosomes, and sister-chromatid cohesion keeps sister chromatids together. However, there is a gap in our
knowledge of the mechanisms that establish and maintain the tethering of homologous chromosomes during
meiosis. Our long-term goal is to define the mechanisms that regulate normal chromosome linkage and
disjunction and identify molecular defects that cause chromosome mis-segregation. Previously, we identified
CHTF18 as a crucial regulator of mammalian meiosis. CHTF18 is a conserved DNA replication protein essential
for sister chromatid cohesion and proper chromosome segregation in yeast, Male and female mice lacking
Chtf18 (Chtf18-/-) are subfertile with impaired gametogenesis. In Chtf18-/- meiotic cells, DNA double-strand
breaks (DSBs) persist, DNA crossovers are decreased, and homologous chromosomes separate prematurely.
We have recently discovered that CHTF18 is required for meiotic chromosome cohesion, a process mediated
by cohesins. We showed that CHTF18 physically interacts with cohesins and regulates their association with
chromatin and their composition during prophase I. Our data support a model in which CHTF18 mediates
cohesins during meiotic DNA replication and recombination to promote crossover formation. However, the
distribution and timing of CHTF18 throughout meiosis is not known because current antibodies pose a significant
limitation. Functional partners with which CHTF18 interact are also not known. This foundational information is
essential to discover how CHTF18 functions at the molecular level. Thus, the objective of this proposal is to
generate and characterize a unique mouse line as a tool to delineate the role of CHTF18 in meiosis. This novel
mouse line will permit us to overcome the limitation of elucidating the CHTF18 mechanism of action caused by
a lack of specific antibodies. We propose to: 1) generate and validate a mouse line that contains an epitope-
tagged allele of Chtf18 (Chtf18FH) and determine the spatiotemporal distribution of CHTF18 in meiosis; and 2)
identify and validate functional partners that interact with CHTF18 in meiosis. Completing this project will
generate an invaluable experimental tool and essential information about CHTF18 function, providing the basis
for studies that investigate how chromosome cohesion is necessary for meiotic recombination and chromosome
segregation. The use of male and female mice will allow us to precisely define the sexually dimorphic roles of
CHTF18 in the regulation and timing of meiosis. By providing novel information about the distribution, timing,
and interacting partners of CHTF18 during key steps of meiosis in spermatocytes and oocytes,...

## Key facts

- **NIH application ID:** 10452959
- **Project number:** 1R03HD105832-01A1
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** KAREN MICHELE BERKOWITZ
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $74,111
- **Award type:** 1
- **Project period:** 2022-02-16 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452959

## Citation

> US National Institutes of Health, RePORTER application 10452959, Generation and characterization of a novel mouse line to elucidate CHTF18 function in male and female meiosis (1R03HD105832-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10452959. Licensed CC0.

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