Abstract
Gamete production is a fundamental process for reproduction; however, exposure to stress, such as increased environmental temperature, can decrease or even interrupt this process, affecting fertility. Thus, the survival of spermatogonial stem cells (SSCs) is crucial for the recovery of spermatogenesis upon stressful situations. Here, we show that the Notch pathway is implicated in such survival, by protecting the SSCs against thermal stress. First, we corroborated the impairment of spermatogenesis under heat stress in medaka, observing an arrest in metaphase I at 10 days of heat treatment, an increase in the number of spermatocytes, and downregulation of ndrg1b and sycp3. In addition, at 30 days of treatment, an interruption of spermatogenesis was observed with a strong loss of spermatocytes and spermatids. Then, the exposure of adult males to thermal stress condition induced apoptosis mainly in spermatogenic and supporting somatic cells, with the exception of the germinal region, where SSCs are located. Concomitantly, the Notch pathway–related genes were upregulated, including the ligands (dll4, jag1-2) and receptors (notch1a-3). Moreover, during thermal stress presenilin enhancer-2 (pen-2), the catalytic subunit of γ-secretase complex of the Notch pathway was restricted to the germinal region of the medaka testis, observed in somatic cells surrounding type A spermatogonia (SGa). The importance of Notch pathway was further supported by an ex vivo approach, in which the inhibition of this pathway activity induced a loss of SSCs. Overall, this study supports the importance of Notch pathways for the protection of SSCs under chronic thermal stress.
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Acknowledgements
We thank Tech. Gabriela C. López for helping with histological preparations. We also thank Dr. Tania Rodriguez for technical support and Tech. Javier Herdman (INTECH) for fish handling. We are grateful to NBRP Medaka (https://shigen.nig.ac.jp/medaka/) for providing HNI (Strain ID: MT835).
Funding
This work was supported by the Agencia Nacional de Promoción Científica y Tecnológica Grant 2501/15 and 1875/18 (to JIF) and CONICET-FAPESP International Cooperation Grant D 2979/16 and 14/50790–0 (to JIF and RSH). ODMA was supported by a PhD scholarship from the National Research Council (CONICET). AFB was supported by an undergraduate scholarship from Universidad Nacional de San Martín (UNSAM). JIF is a member of the Research Scientist Career at the CONICET.
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ODMA: conceptualization, methodology, analysis; AFB: methodology and visualization; RSH: funding acquisition, conceptualization, writing — reviewing and editing, JIF: funding acquisition, conceptualization, investigation, supervision; writing — original draft preparation, writing — reviewing and editing.
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Table Supplement 1
Primers sequences, ENSEMBL and NCBI accession numbers and the respective references of each gene. (DOCX 26 kb)
Supplementary Fig. S1
Cycle threshold (Ct) of reference genes rpl7 and ef-1a. Cycle threshold of rpl7 and ef-1a of testis tissue from in vivo (A) and explant incubated at NT and HT (B). Cts quantifications were compared by one-way analysis of variance (ANOVA), followed by Tukey´s multiple comparisons test, for comparing the mean of each column with the mean of every other column. p-values are indicated when differences between treatment at the same sampling day differ significantly (P<0.05). NS, not statistically significant. (PNG 348 kb)
Supplementary Fig. S2
Time and dose optimization for the ex vivo experiment. Time exposure curve of p53 transcript abundance in testis explants incubated at control (NT – 25º C, light grey) and high (HT – 33º C, dark grey) temperature, with sampling at 0, 3, 12 and 24 hours (A). DAPT doses response: Transcript abundance levels of hes1 (Notch pathway cis target genes) in adult testis explants incubated during 24 hours at 0, 6.25, 12.5, 25, 50 and 100 μM of DAPT (γ-secretase inhibitor) (B). Transcript abundance quantification was performed using the geometric mean method and p53 and hes1 values were normalized against geometric mean of reference genes rpl7 and ef-1a. p-values are indicated when transcript abundance between treatment at the same sampling day differs significantly (P<0.05). (PNG 342 kb)
Supplementary Fig. S3
Graphical abstract. The activation of Notch pathway in somatic cell of the testis induces the inhibition of spermatogenesis under heat temperature exposure. SGa: type A spermatogonia; SGb: type b spermatogonia; Sc: spermatocyte; Sd: spermatid; Sz: spermatozoa. (PNG 647 kb)
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Moreno Acosta, O.D., Boan, A.F., Hattori, R.S. et al. Notch pathway is required for protection against heat stress in spermatogonial stem cells in medaka. Fish Physiol Biochem 49, 487–500 (2023). https://doi.org/10.1007/s10695-023-01200-w
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DOI: https://doi.org/10.1007/s10695-023-01200-w