The power of mouse genetics to study spermatogenesis

Abstract

Approximately 80 million people worldwide are infertile, and nearly half of all infertility cases are attributed to a male factor. Therefore, progress in reproductive genetics becomes crucial for future diagnosis and treatment of infertility. In recent years, enormous progress has been made in this field. More than 400 mutant mouse models with specific reproductive abnormalities have been produced, and numerous human association studies have been discovered. However, the translation of basic science findings to clinical practice remains protracted, with only modest progress in the application of novel findings to clinical genetic testing and cures. To date, the most significant findings in male infertility remain numeric and structural chromosomal abnormalities and Y-chromosome microdeletions in infertile men. Thus, we anticipate that future genetic investigations will focus on infertile men with a normal somatic karyotype but with various spermatozoal defects, like insufficient production of spermatozoa (oligozoospermia), inadequate motility (asthenozoospermia), abnormal morphology (teratozoospermia), or combinations of these defects. Ultimately, basic advances in mammalian nonhuman reproduction will translate to clinical advances in human reproduction and testing for infertile humans, thereby helping to improve diagnostics and health care for infertile patients.

Figure 1

Essential molecules regulating self-renewal of spermatogonial stem cell (SSC). Glial cell line–derived neutrophic factor (GDNF) stimulates SSC self-renewal, and basic fibroblast growth factor (bFGF) and colony-stimulating factor 1 (CSF1) enhance this activity. Transcriptional repressor, encoded by B-cell chronic lymphocytic leukemia/lymphoma 6, member b (Bcl6b) and the transcription factors Ets variant 5 (Etv5) and LIM homeobox 1 (Lhx1), are activated by the GDNF stimuli. Independently from GDNF signaling, the transcriptional repressor promyelocytic leukemia zinc finger; (PLZF; also known as ZBTB16 and ZFP145) and transcription factor TATA box-binding protein–associated factor (TAF4b) regulate SSC self-renewal.

Figure 2

(A) The localization of TEX14 in the testis. Immunofluorescence using anti–testis-expressed gene 14 (TEX14) antibody shows that TEX14 localizes to intercellular bridge. Red, TEX14; blue, 4′,6-diamidino-2-phenylindole. The tissue is from a 6-week-old male mouse testis. Inset shows a representative intercellular bridge at a high magnification. (B) A summary of intercellular bridges. In testes, the A-type single (A_s) spermatogonium is the stem cell. The daughter cells of A_s spermatogonia are self-renewed A_s spermatogonia without intercellular bridges and A-paired (A_pr) spermatogonia interconnecting by intercellular bridges. All differentiating germ cells, which are present after the A_s cell differentiates to form an A_pr spermatogonia and through the haploid germ cell stages, are connected by intercellular bridges. TEX14 localizes initially to the midbody during cytokinesis, and its presence results in stable intercellular bridges in differentiating germ cells. TEX14 is a specific marker for intercellular bridges, the differentiation process, and the initiation of the spermatogenesis pathway. Details of the model are as follows: black arrow, dividing cell; orange arrow, maturing cell; red ring, midbody and TEX14; purple bar, intercellular bridge; turquoise blue and bright green circles, cytoplasm of stem cell and differentiating germ cell; blue, maturing nucleus during spermiogenesis.

Figure 3

Distribution of identified KLHL10 mutations among categories of sperm concentration in infertile men. Three major categories are shown in the upper part of the figure: severe (red) and moderate (pink) oligozoospermia, and normozoospermia (green). The lower part shows all of the KLHL10-identified mutations with respect to their corresponding position in the KLHL10 protein. Mutations present above the protein are only present in oligozoospermic patients, whereas those depicted below the protein are also observed in normozoospermic patients (believed to be rare polymorphisms). Splicing* denotes splicing KLHL10 mutation, c.1302+121_124del4bp. Known functional domains of the KLHL10 protein are shown by different colors and named after their respective domains, as BTB, BACK, and K1–K6 (Kelch motifs 1–6).