E-cadherin maintains the undifferentiated state of mouse spermatogonial progenitor cells via β-catenin

Weixiang Song; Danchen Zhang; Jiaqi Mi; Wenfei Du; Yang Yang; Rong Chen; Cong Tian; Xiaodong Zhao; Kang Zou

doi:10.1186/s13578-022-00880-w

E-cadherin maintains the undifferentiated state of mouse spermatogonial progenitor cells via β-catenin

Cell Biosci. 2022 Sep 1;12(1):141. doi: 10.1186/s13578-022-00880-w.

Authors

Weixiang Song^#^{1

2}, Danchen Zhang^#^{1

2}, Jiaqi Mi^#³, Wenfei Du⁴, Yang Yang^{1

2}, Rong Chen^{1

2}, Cong Tian^{1

2}, Xiaodong Zhao⁵, Kang Zou^{6

7}

Affiliations

¹ Germline Stem Cells and Microenvironment Lab, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.
² Stem Cell Research and Translation Center, Nanjing Agricultural University, Nanjing, 210095, China.
³ Department of Cancer Biology, Cancer Center and Beckman Research Institute, City of Hope, 91010, Duarte, USA.
⁴ Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Bio-medicine, Shanghai Jiao Tong University, Shanghai, 200240, China.
⁵ Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Bio-medicine, Shanghai Jiao Tong University, Shanghai, 200240, China. xiaodongzhao@sjtu.edu.cn.
⁶ Germline Stem Cells and Microenvironment Lab, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China. kangzou@njau.edu.cn.
⁷ Stem Cell Research and Translation Center, Nanjing Agricultural University, Nanjing, 210095, China. kangzou@njau.edu.cn.

^# Contributed equally.

Abstract

Background: Cadherins play a pivotal role in facilitating intercellular interactions between spermatogonial progenitor cells (SPCs) and their surrounding microenvironment. Specifically, E-cadherin serves as a cellular marker of SPCs in many species. Depletion of E-cadherin in mouse SPCs showed no obvious effect on SPCs homing and spermatogenesis.

Results: Here, we investigated the regulatory role of E-cadherin in regulating SPCs fate. Specific deletion of E-cadherin in germ cells was shown to promote SPCs differentiation, evidencing by reduced PLZF⁺ population and increased c-Kit⁺ population in mouse testes. E-cadherin loss down-regulated the expression level of β-catenin, leading to the reduced β-catenin in nuclear localization for transcriptional activity. Remarkably, increasing expression level of Cadherin-22 (CDH22) appeared specifically after E-cadherin deletion, indicating CDH22 played a synergistic effect with E-cadherin in SPCs. By searching for the binding partners of β-catenin, Lymphoid enhancer-binding factor 1 (LEF1), T-cell factor (TCF3), histone deacetylase 4 (HDAC4) and signal transducer and activator 3 (STAT3) were identified as suppressors of SPCs differentiation by regulating acetylation of differentiation genes with PLZF.

Conclusions: Two surface markers of SPCs, E-cadherin and Cadherin-22, synergically maintain the undifferentiation of SPCs via the pivotal intermediate molecule β-catenin. LEF1, TCF3, STAT3 and HDAC4 were identified as co-regulatory factors of β-catenin in regulation of SPC fate. These observations revealed a novel regulatory pattern of cadherins on SPCs fate.

Keywords: E-cadherin; SPC differentiation; Transcription regulation; ß-catenin.

Grants and funding

JBGS[2021]024/Jiangsu seed industry revitalization project