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Deciphering the regulatory networks of human male germline development from embryo to adulthood.

Jun Chen,Xinyan Yang,Manman Cui,Zhaokai Yao,Zhaoxiang Ouyang,Zihang Qu,Yingying Huang,Yongtong Zhu,Jiexiang Zhao,Gang Chang

Published 2025 in Biochimica et Biophysica Acta - Molecular Basis of Disease

ABSTRACT

Male germline development is crucial for the proper establishment of spermatogonial stem cell pool and life-long production of spermatozoa, but the full-term developmental profiling of human male germline is not fully understood. Here, by integrating 92,488 human testicular cells spanning from six-week-old embryo to old men, we constructed a comprehensive human male germ cell atlas. Further analysis found that the precursor of undifferentiated spermatogonia underwent regulatory network reconfiguration starting from week 7 post-fertilization, accompanied by WNT6-FZD3/LRP6-JUN/MYC signaling axis. And JUN and MYC were revealed to be candidate core transcription factors that might inhibit spermatogonia differentiation. In addition, the activation of ANGPTL signaling played a role in the maintenance of human spermatogonial stem cell. Finally, by interrogating the scRNA-seq datasets from several types of idiopathic non-obstructive azoospermia (iNOA) patients, we identified several iNOA-dysregulated genes such as CAPN3, FTMT, IZUMO2 and LACE1, which were significantly down-regulated in round spermatids of iNOA patients. Collectively, our work constructed a comprehensive human male germ cell development atlas, revealing the factors that might regulate male germline development and providing iNOA-dysregulated genes for future clinical diagnosis.

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