Genetic and genomic insights into male reproductive tract development

Genetic and genomic analysis continues to drive important insights into male reproductive tract (MRT) development. Here, we briefly review normal MRT development, highlighting recent discoveries of cell types and cellular processes delivered by single-cell sequencing. We report a systematic review of phenotype terms and genes linked to MRT development, identifying 35 terms from the Human Phenotype Ontology associated with 269 unique genes. A parallel review of mouse data revealed differences in the phenotype terms available and the number and identity of genes linked to MRT defects, indicating opportunities for harmonization of knowledge. We used a published single-cell atlas of the developing testis to characterize the regulation of MRT genes across cell types and stages of fetal testis development. Single-cell RNA sequencing data support the conclusion that Leydig cells and Sertoli cells are the primary testicular cell types expressing MRT genes. Furthermore, we find post-conception weeks 6, 8, and 16 to be the key points of upregulation of testicular MRT genes. New advances, especially in imaging and spatially resolved molecular measurements, provide exciting prospects for MRT research and diagnosis, and we expect rapid progress in the coming years. Continued investigation in this space is essential to understand the genetic basis of MRT development and how MRT defects are related to medical outcomes in adult life.