ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 6.5 | DOI: 10.1530/ey.18.6.5

ESPEYB18 6. Differences of Sexual Development (DSD) and Gender Dysphoria (GD) Basic and Genetic Research of DSD (6 abstracts)

6.5. Applying Single-Cell Analysis to Gonadogenesis and DSDs (Disorders/Differences of Sex Development)

Estermann MA & Smith CA

Int J Mol Sci. 2020 Sep 10;21(18). pii: E6614. doi: 10.3390/ijms21186614. PMID: 32927658

This review first summarises current molecular knowledge of gonadal development and related DSDs, and then overviews methods of single-cell sequencing (sc-seq) technologies and their applications and findings for healthy gonads and disease states. Recent studies are listed in two tables and major findings for normal tissues, DSD, infertility and cancers are shortly described. The advantages, challenges, and limitations of sc-seq and multi-omics approaches for elucidating and understanding the complex biology of the gonads from conception to aging are discussed.

Sc-seq was the chosen ‘Method of the year 2013’ by Nature (1). Meanwhile its use in research to understand complex developmental biological processes and disease states and mechanisms expands, while its application in routine investigation is pending. Important for its successful wider application is the comprehensive collection of normal data of all organ systems in a spatio-temporal fashion. This task is currently ongoing in the Human Cell Atlas project ( and not yet completed for the human gonads. Sc-seq comprises sc genomics, transcriptomics, and proteomics; combined to sc multi-omics it allows unique insights into genotype-phenotype correlation and developmental processes. So far, sc seq studies on normal human, primate and non-primate gonadal tissues have largely confirmed previous findings, but also revealed novel details that had been missed in previous tissue bulk analyses. For instance, it has confirmed that the mutually exclusive sexually dimorphic program of the female and male gonads must be actively maintained throughout life (2), otherwise trans-differentiation will occur (3-5). On the other hand, sc-seq studies of the adult human testis discovered pericytes as a novel cell population that seem to act as multi-functional cells of the microvasculature (6). Currently, sc-seq multi-omics studies on DSD gonads are still missing, but they bear the potential to provide deep insight into genotype-phenotype correlation and disease mechanisms. Once obstacles, such as tissue sample availability and preservation issues, costs, and lack of normal datasets for comparison have been overcome, sc-seq omics might become a powerful tool for clinical applications improving diagnostic and therapeutic possibilities.

Reference: 1. “Method of the year 2013”. Nature Methods. 11(1): 1. January 2014. doi: 10.1038/nmeth.2801. PMID 24524124.2. Lindeman, R.E.; Gearhart, M.D.; Minkina, A.; Krentz, A.D.; Bardwell, V.J.; Zarkower, D. Sexual cell-fate reprogramming in the ovary by DMRT1. Curr. Biol. 2015, 25, 764–771.3. Barrionuevo, F.J.; Hurtado, A.; Kim, G.J.; Real, F.M.; Bakkali, M.; Kopp, J.L.; Sander, M.; Scherer, G.; Burgos, M.; Jimenez, R. Sox9 and Sox8 protect the adult testis from male-to-female genetic reprogramming and complete degeneration. eLife 2016, 5.4. Matson, C.K.; Murphy, M.W.; Sarver, A.L.; Griswold, M.D.; Bardwell, V.J.; Zarkower, D. DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature 2011, 476, 101–104.5. Uhlenhaut, N.H.; Jakob, S.; Anlag, K.; Eisenberger, T.; Sekido, R.; Kress, J.; Treier, A.C.; Klugmann, C.; Klasen, C.; Holter, N.I.; et al. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell 2009, 139, 1130–1142.6. Shami, A.N.; Zheng, X.; Munyoki, S.K.; Ma, Q.; Manske, G.L.; Green, C.D.; Sukhwani, M.; Orwig, K.E.; Li, J.Z.; Hammoud, S.S. Single-Cell RNA Sequencing of Human, Macaque, and Mouse Testes Uncovers Conserved and Divergent Features of Mammalian Spermatogenesis. Dev. Cell 2020.

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