Survival Motor Neuron Protein Participates in Mouse Germ Cell Development and Spermatogonium Maintenance.

Wei-Fang Chang,Li-Ying Sung,Jie Xu,Jing Hsu,Hsiu-Mei Hsieh-Li,Ji-Long Liu,Chung-Hao Lu,Tzu-Ying Lin,Yuh-Ming Hwu

doi:10.3390/ijms21030794

Abstract

The defective human survival motor neuron 1 (SMN1) gene leads to spinal muscular atrophy (SMA), the most common genetic cause of infant mortality. We previously reported that loss of SMN results in rapid differentiation of Drosophila germline stem cells and mouse embryonic stem cells (ESCs), indicating that SMN also plays important roles in germ cell development and stem cell biology. Here, we show that in healthy mice, SMN is highly expressed in the gonadal tissues, prepubertal spermatogonia, and adult spermatocytes, whereas low SMN expression is found in differentiated spermatid and sperm. In SMA-like mice, the growth of testis tissues is retarded, accompanied with gamete development abnormalities and loss of the spermatogonia-specific marker. Consistently, knockdown of Smn1 in spermatogonial stem cells (SSCs) leads to a compromised regeneration capacity in vitro and in vivo in transplantation experiments. In SMA-like mice, apoptosis and accumulation of the R-loop structure were significantly elevated, indicating that SMN plays a critical role in the survival of male germ cells. The present work demonstrates that SMN, in addition to its critical roles in neuronal development, participates in mouse germ cell and spermatogonium maintenance.

Highlights

We and others reported that the levels of SMN protein correlate with the capacities of stem cell proliferation and differentiation in Drosophila [1] and mice [2]
The testis of 2- and 8-week-old male mice were used to isolate spermatogonia and spermatocyte based on the level of Thy-1 Cell Surface Antigen (THY1) expression by fluorescence-activated cell sorting (FACS)
The spermatogonia marker promyelocytic leukemia zinc-finger (PLZF) in 8-week-old mice was expressed with a high percentage in sorted THY1+ spermatogonia cells (60%); whereas THY1−FSCHi cells showed a low percentage of PLZF signal (7.6%) and high percentage of meiotic marker synaptonemal complex protein 3 (SCP3) expression (91%) (Figure 1B) [12,13,14]

Summary

Introduction

We and others reported that the levels of SMN protein correlate with the capacities of stem cell proliferation and differentiation in Drosophila [1] and mice [2]. In mouse embryonic stem cells (ESCs), delayed cell growth and increased differentiation signals took place after knockdown of Smn1 [2]. These findings suggest that SMN plays important roles in germ cell development and pluripotent stem cell maintenance, in addition to its well-known roles during neuronal development. It has been reported that Setx knockout mice are defective in spermatogenesis, meiotic recombination, and meiotic sex chromosome inactivation [11]. These findings suggest that SMN plays important roles in germ cell development and stem cell biology

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