RESUMEN

Leydig cells are essential components of testicular interstitial tissue and serve as a primary source of androgen in males. A functional deficiency in Leydig cells often causes severe reproductive disorders; however, the transcriptional programs underlying the fate decisions and steroidogenesis of these cells have not been fully defined. In this study, we report that the homeodomain transcription factor PBX1 is a master regulator of Leydig cell differentiation and testosterone production in mice. PBX1 was highly expressed in Leydig cells and peritubular myoid cells in the adult testis. Conditional deletion of Pbx1 in Leydig cells caused spermatogenic defects and complete sterility. Histological examinations revealed that Pbx1 deletion impaired testicular structure and led to disorganization of the seminiferous tubules. Single-cell RNA-seq analysis revealed that loss of Pbx1 function affected the fate decisions of progenitor Leydig cells and altered the transcription of genes associated with testosterone synthesis in the adult testis. Pbx1 directly regulates the transcription of genes that play important roles in steroidogenesis (Prlr, Nr2f2 and Nedd4). Further analysis demonstrated that deletion of Pbx1 leads to a significant decrease in testosterone levels, accompanied by increases in pregnenolone, androstenedione and luteinizing hormone. Collectively, our data revealed that PBX1 is indispensable for maintaining Leydig cell function. These findings provide insights into testicular dysgenesis and the regulation of hormone secretion in Leydig cells.

Asunto(s)

Infertilidad Masculina , Células Intersticiales del Testículo , Factor de Transcripción 1 de la Leucemia de Células Pre-B , Testículo , Testosterona , Animales , Masculino , Células Intersticiales del Testículo/metabolismo , Células Intersticiales del Testículo/patología , Factor de Transcripción 1 de la Leucemia de Células Pre-B/metabolismo , Factor de Transcripción 1 de la Leucemia de Células Pre-B/genética , Ratones , Testosterona/metabolismo , Testículo/metabolismo , Testículo/patología , Infertilidad Masculina/genética , Infertilidad Masculina/patología , Infertilidad Masculina/metabolismo , Diferenciación Celular/genética , Espermatogénesis/genética , Ratones Endogámicos C57BL , Ratones Noqueados

RESUMEN

BACKGROUND: Spermatogonial stem cells (SSCs) provide a foundation for robust and continual spermatogenesis in mammals. SSCs self-renew to maintain a functional stem cell pool and differentiate to supply committed progenitors. Metabolism acts as a crucial determinant of stem cell fates; however, factors linking metabolic programs to SSC development and maintenance are poorly understood. RESULTS: We analyzed the chromatin accessibility of undifferentiated spermatogonia at the single-cell level and identified 37 positive TF regulators that may have potential roles in dictating SSC fates. The transcription factor E4F1 is expressed in spermatogonia, and its conditional deletion in mouse germ cells results in progressive loss of the entire undifferentiated spermatogonial pool. Single-cell RNA-seq analysis of control and E4f1-deficient spermatogonia revealed that E4F1 acts as a key regulator of mitochondrial function. E4F1 binds to promotors of genes that encode components of the mitochondrial respiratory chain, including Ndufs5, Cox7a2, Cox6c, and Dnajc19. Loss of E4f1 function caused abnormal mitochondrial morphology and defects in fatty acid metabolism; as a result, undifferentiated spermatogonia were gradually lost due to cell cycle arrest and elevated apoptosis. Deletion of p53 in E4f1-deficient germ cells only temporarily prevented spermatogonial loss but did not rescue the defects in SSC maintenance. CONCLUSIONS: Emerging evidence indicates that metabolic signals dictate stem cell fate decisions. In this study, we identified a list of transcription regulators that have potential roles in the fate transitions of undifferentiated spermatogonia in mice. Functional experiments demonstrated that the E4F1-mediated transcription program is a crucial regulator of metabolism and SSC fate decisions in mammals.

RESUMEN

Atom gravimeters use locked lasers to manipulate atoms to achieve high-precision gravity measurements. Frequency modulation spectroscopy (FMS) is an accurate method of optical heterodyne spectroscopy, capable of the sensitive and rapid frequency locking of the laser. Because of the effective absorption coefficient, Doppler broadening and susceptibility depend on temperature, and the signal-to-noise ratio (SNR) of the spectroscopy could be affected by temperature. We present a detailed study of the influence of the temperature on FMS in atom gravimeters, and the experimental results show that the SNR of the spectroscopy is dependent on temperature. In this paper, the frequency of the reference laser is locked by tracking the set point of the fringe slope of FMS. The influence of the frequency-locking noise of the reference laser on the sensitivity of the atom gravimeter is investigated by changing the temperature of the Rb cell without extra operations. The method presented here could be useful for improving the sensitivity of quantum sensors that require laser spectroscopic techniques.