Monday, May 13, 2024 5/13/2024

Origin and functional significance of the spermatogonial stem cell transcriptome barcode

Award Number: R01HD090007
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Male fertility in mammals depends on formation of a foundational SSC pool in the testis. Defects in formation or maintenance of SSCs are considered primary causes of Sertoli cell-only (SCO) syndrome, which results in non-obstructive azoospermia (NOA) and male infertility. Rodent SSCs arise from prospermatogonia in the first week of life, yet the mechanisms responsible for their specification have eluded the male reproduction field for decades. In this project, we will interrogate two alternate hypotheses: 1- that foundational SSCs are predetermined and emerge from a precursor subpopulation expressing a unique transcriptome barcode (“predetermination”), or 2- that SSCs are induced from prospermatogonia such that unique transcriptomes emerge from equipotent precursors (“selection”). By testing these alternate hypotheses, we will address a critical gap in our knowledge of how the foundation of spermatogenesis is formed. Results of preliminary studies demonstrated that P6 ID4-EGFP+ spermatogonia exhibit gene expression heterogeneity which defined discrete subpopulations, including those highly-enriched and depleted for foundational SSCs. We defined a distinct SSC transcriptome barcode which was identified based on the unique gene expression signature revealed by single-cell RNA-seq analyses of a population of nearly pure SSCs. This SSC barcode also appeared to also be expressed by a subpopulation of male germ cells isolated from fetal and neonatal male germ cells. Lastly, we found that enriched populations of human undifferentiated spermatogonia exhibited similar heterogeneity to mouse spermatogonia which could enable future discernment of the elusive human SSC. These results suggest that the SSC barcode is conserved through mouse male germline development could potentially be used to broadly distinguish mammalian foundational SSCs. We propose three Specific Aims to test the alternate predetermination and selection hypotheses by examining the temporal origin the SSC barcode and its functional significance to the formation of the SSC pool. Aim 1 will distinguish emergence of cells expressing the SSC barcode among individual mouse germ cells from late fetal through early postnatal testis development and correlate appearance of this phenotype with SSC function by transplant. Aim 2 will determine whether fetal germ cells expressing this SSC barcode are required for formation of the foundational SSC pool using lineage ablation and tracing methods in mice. Aim 3 will establish whether the mouse SSC barcode is conserved in higher primates (baboons and humans) and ask if its temporal emergence in the primate parallels that seen in the mouse. Throughout this proposal, we will examine gene expression with single-cell resolution and leverage SSC transplantation and lineage tracing/ablation to provide pivotal functional readouts of SSC fate. The proposed studies will allow us to address a key question in male reproduction– how is the pool of SSCs established?


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: 2024 ( Subtotal = $0 )
2024	2021	THE UNIVERSITY OF TEXAS AT SAN ANTONIO	1 UTSA CIR	SAN ANTONIO	TX	78249	BEXAR	USA	Child Health and Human Development Extramural Research	000	5	12/27/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $308,161 )
2021	2021	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Child Health and Human Development Extramural Research	000	5	3/16/2021	NON-COMPETING CONTINUATION	$308,161
														Subtotal = $308,161

Issue Date FY: 2020 ( Subtotal = $323,872 )
2020	2020	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Child Health and Human Development Extramural Research	000	4	4/9/2020	NON-COMPETING CONTINUATION	$323,872
														Subtotal = $323,872

Issue Date FY: 2019 ( Subtotal = $303,016 )
2019	2019	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Child Health and Human Development Extramural Research	000	3	5/1/2019	NON-COMPETING CONTINUATION	$303,016
														Subtotal = $303,016

Issue Date FY: 2018 ( Subtotal = $303,016 )
2018	2018	UNIVERSITY OF TEXAS AT SAN ANTONIO, THE	1 UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Child Health and Human Development Extramural Research	000	2	4/20/2018	NON-COMPETING CONTINUATION	$303,016
														Subtotal = $303,016

Issue Date FY: 2017 ( Subtotal = $303,016 )
2017	2017	UNIVERSITY OF TEXAS AT SAN ANTONIO	ONE UTSA CIRCLE	SAN ANTONIO	TX	78249	BEXAR	USA	Child Health and Human Development Extramural Research	000	1	6/30/2017	NEW	$303,016
														Subtotal = $303,016

Grand Total All Awards = $1,541,081

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Origin and functional significance of the spermatogonial stem cell transcriptome barcode

Award Number: R01HD090007

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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