What is it about?
Development of the lower urogenital tract is complex and research progress to identify crucial regulatory genes governing urogenital development is hampered by the lack of a streamlined screening system. The present study describes a tool, in the form of a mouse model, which can screen for likely regulators of embryonic sexual development. In this model, the androgen receptor adds a permanent mark to DNA near the genes that it is regulating. These marks accumulate and can be read with sequencing to identify nearby genes. We focused on transcription factor hits, which are critical during development because they regulate the expression of other genes. Through extensive validation at the levels of gene expression, functional relevance and clinical relevance, thirty-one top-tier candidates were identified, including Sall1, whose function in urogenital development was verified by knockout mouse.
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Why is it important?
Congenital structural anomalies of the reproductive and lower genitourinary systems comprise some of the most common yet most socially stigmatized congenital phenotypes. Despite its prevalence, research progress in identifying causative genes for these developmental anomalies has been slow due to the lack of a screening system to quickly identify crucial genes. This work paves way for rapid identification of genes playing crucial roles in directing urogenital development by combining both in vivo and in vitro approaches, and by integrating both mouse and human genetic data. Following this line of investigation, it is expected that the process of disease gene identification affecting urogenital development should be dramatically accelerated.
Perspectives
This can only be described as a mammoth study. It elegantly combines novel in vivo tools with in vitro validations and in vivo proof of principle experiments. It maps a massive network of genes and ranks them to provide future researchers with manageable hypotheses and justification for knockout model investments. It also sets the stage for the continued use of in vivo protein-DNA interaction mapping tools. The identification of Sall1 as a critical lower urogenital regulator is just the first of what will surely be many branches of discovery with its trunks and roots in this screening study. It was a privilege to work on this paper and I am grateful to my colleagues for their encouragement and patience.
Meade Haller
Washington University in Saint Louis
Read the Original
This page is a summary of: Streamlined identification of clinically and functionally relevant genetic regulators of lower-tract urogenital development, Proceedings of the National Academy of Sciences, February 2024, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2309466121.
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