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Investigating how germline sexual identity controls sex-specific gene expression

Award Number: F31HD115364
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 11/01/2024
PERIOD OF PERFORMANCE END DATE: 10/31/2027

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Investigating how germline sexual identity controls sex-specific gene expression - PROJECT ABSTRACT To develop functioning gametes, both the germ cells and somatic cells of the gonad must determine their sexual identity. While sex determination and sex-specific gene expression are well characterized in the somatic gonad of Drosophila, little is known about how germ cells determine their sex. The RNA binding protein Sex lethal (Sxl) has been shown to be master regulator of female somatic sex determination. Sxl is also important in the germline, where it is necessary and sufficient for female identity. However, autonomous sex determination downstream of Sxl is not well characterized in the germline. Interestingly, germline sex determination is also regulated non-autonomously via somatic signals. How sex determination in the germline is regulated by a combination of autonomous cues, downstream of Sxl, and non-autonomous cues, based on somatic cell signaling, is unknown and of great interest to the field. I will examine expression of Tdrd5l (Tudor domain-containing protein 5-like), a gene discovered by our lab, which is expressed in a male-specific manner in the undifferentiated germline and is important for male germline sexual identity. Tdrd5l RNA is initially expressed in the embryonic germline of both sexes, but subsequently becomes male-specific at the third larval instar (L3) stage by an unknown mechanism. Preliminary data show that a Tdrd5l-GFP transcriptional reporter is expressed in a male-specific manner during the L3 stage, while sex-specific expression of Tdrd5l RNA in developing germ cells is independent of Sxl. However, we have found that a male soma is sufficient to drive expression of Tdrd5l RNA in female germ cells. Interestingly, Tdrd5l is regulated independently of JAK/STAT signaling, which is the key male-specific signal regulating germline gene expression. Altogether, our study of Tdrd5l regulation indicates that a previously unidentified signal from the somatic gonad to the germline regulates sex-specific germline gene expression. In the adult gonad, expression of Tdrd5l is repressed in undifferentiated female germ cells by the RNA binding protein Sex lethal (Sxl). We have found that deletion of possible Sxl binding sites in the Tdrd5l RNA causes derepression of Tdrd5l protein expression, indicating that part of the sex-specific regulation is post- transcriptional. However, whether Sxl directly binds the Tdrd5l RNA is unknown, as is the mechanism by which Sxl regulates Tdrd5l expression. Thus, I will investigate how Sxl post-transcriptionally regulatesTdrd5l expression, using deletions of each binding site to determine Sxl’s germline role. Together, a study of how Tdrd5l is regulated both transcriptionally and post-transcriptionally in a sex- specific manner will provide insight into the multiple levels by which sex-specific gene expression is regulated in the germline. Understanding sex-specific gene expression in the germline will further our understanding of improper germline development leading to infertility and provide insight into developing new fertility treatments.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $49,538 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	2	12/5/2025	NON-COMPETING CONTINUATION	$49,538
														Subtotal = $49,538

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	1	9/19/2024	NEW	$48,974
														Subtotal = $48,974

Grand Total All Awards = $98,512

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Investigating how germline sexual identity controls sex-specific gene expression

Award Number: F31HD115364

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 11/01/2024

PERIOD OF PERFORMANCE END DATE: 10/31/2027

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