Julia Sorkin

Germ cell connectivity via intercellular bridges is a widely conserved feature across metazoans. However, its functional significance is poorly understood. Intercellular bridges are essential for fertility in male mice as genetic ablation of a critical bridge component, TEX14, causes spermatogenic failure, but the underlying reasons are unknown. Here we utilized a Tex14 hypomorph with reduced intercellular bridges along with Tex14-null mice that completely lack bridges to examine the roles of germ cell connectivity during spermatogenesis. We report that in males deficient for TEX14 and intercellular bridges, germ cells fail to complete meiotic DNA replication, synapsis and meiotic double-strand break repair. They also derepress retrotransposons and accumulate retrotransposon-encoded proteins during meiosis. Single-cell RNA-sequencing confirms sharing of transcripts between wild-type spermatids and demonstrates its partial attenuation in Tex14 hypomorphs, indicating that intercellular bridges enable cytoplasmic exchange between connected germ cells in testes. Our findings suggest that regulation of meiosis is non-cell-intrinsic and inform a model in which intercellular bridges influence critical meiotic events and protect germline genome integrity during spermatogenesis.

ABSTRACT The human genome contains 24 gag -like capsid genes derived from deactivated retrotransposons conserved among eutherians. Although some of their encoded proteins retain the ability to form capsids and even transfer cargo, their fitness benefit has remained elusive. Here we show that the gag -like genes PNMA1 and PNMA4 support reproductive capacity. Six-week-old mice lacking either Pnma1 or Pnma4 are indistinguishable from wild-type littermates, but by six months the mutant mice become prematurely subfertile, with precipitous drops in sex hormone levels, gonadal atrophy, and abdominal obesity; overall they produce markedly fewer offspring than controls. Analysis of donated human ovaries shows that expression of both genes declines normally with aging, while several PNMA1 and PNMA4 variants identified in genome-wide association studies are causally associated with low testosterone, altered puberty onset, or obesity. These findings expand our understanding of factors that maintain human reproductive health and lend insight into the domestication of retrotransposon-derived genes.