Determining the Mechanisms Responsible for Infertility in Homozygous Males of the 5XE Mutant Mouse Model

Mae D'Ambra

Document Type

Article

Publication Date

8-9-2024

Keywords

JMG

JAX Location

In: Student Reports, Summer 2024, The Jackson Laboratory

Abstract

A Chromosome (Ch) 13 quantitative trait locus (QTL) phenotypically influences numerous biological processes ranging from dactylaplasia to cleft lip and palate in mice (Byers et al., 2021). The Baker Lab created the 5XE mouse model – a DBA/2J (D2) background with a C57BL/6J (B6) congenic region on Ch 13 containing thirteen KRAB zinc finger proteins (KZFPs) – to study this QTL, and discovered homozygous (hom) males were completely infertile. In an attempt to locate the stage of spermatogenic failure, we immunostained 5XE spermatocyte spreads for double-strand breaks (yH2AX) and chromosome synapsis (SYCP3). Primary interpretations concluded DNA damage was restricted solely to the sex body during early meiosis yet, upon experimental replication, I discovered hom 5XE sex chromosomes fail to transition from mid- to late-pachytene during meiotic prophase I. The presence of an early meiotic block was also supported by testis seminiferous tubule counts, as week-ten homozygous 5XE testis cross sections were smaller in diameter and contained significantly less spermatozoa by sexual maturity compared to their fertile, heterozygous (het) counterparts. Therefore, 5XE infertility most likely results from a mid-pachytene meiotic block, manifested by inadequate KZFP regulation of local transposable elements (TEs) that disrupt specific fertility development genes of the D2 genome.

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