# Investigating Germline Sex Determination

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $405,469

## Abstract

Investigating Germline Sex Determination
Establishing sex-specific germ cell identity is critical for development of sperm and eggs and perpetuation of
the species. Cells are initially specified as primordial germ cells (PGCs), and then germline sex determination
establishes a male or female germline identity. While sex determination is understood in the somatic cells of
some animals, how germline sexual identity is established is largely unknown. In most animals, germline sex
determination is regulated by signals from the surrounding somatic gonad. However, in some animals, like
humans and Drosophila, the germ cell’s sex chromosome constitution is also important. Thus, the sex of the
soma and germline must match for proper gametogenesis to proceed. How somatic signals interface with germ
cell autonomous cues to achieve proper sex determination is also unknown.
Many aspects of germ cell identity are regulated at the post-transcriptional level. The RNA binding protein Sex
lethal (Sxl) is activated in XX germ cells and is necessary and sufficient for germline sex determination in
Drosophila, but little is known about how it acts to control this process. Further, a germ cell-specific
transcriptional program must also be established in order for Sxl to influence this program in a sex-specific
manner. Lastly, Sxl in the germline must combine with signals from the soma to determine germline sexual
identity.
Recently, we have made two important discoveries that illuminate these processes. First, an important signal
from the soma that promotes male germline identity acts through the Jak/Stat pathway. As this pathway is also
used to regulate development of the somatic gonad in both sexes, Sxl acts in female germ cells to block the
Jak/Stat pathway and preserve female germline identity. Second, we have discovered a new tudor-domain
protein, Tdrd5l, that is important for male identity in the germline and is a putative target for repression by Sxl
in the female germline. Tdrd5l defines a novel germline granule, the “Tdrd5l body” and our preliminary data
indicates that Tdrd5l regulates germline gene expression at the post-transcriptional level. We propose to use
Tdrd5l as a model for understanding the regulation of gene expression in the germline and to investigate the
mechanism of action of the “Tdrd5l body”.

## Key facts

- **NIH application ID:** 10860131
- **Project number:** 1R01GM154088-01
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Mark B Van Doren
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $405,469
- **Award type:** 1
- **Project period:** 2024-07-12 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10860131

## Citation

> US National Institutes of Health, RePORTER application 10860131, Investigating Germline Sex Determination (1R01GM154088-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10860131. Licensed CC0.

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