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.
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.
摘要：
背景：钙黏着蛋白在促进精原祖细胞（SPC）及其周围微环境之间的细胞间相互作用中起关键作用。具体来说,E-钙粘蛋白在许多物种中用作SPCs的细胞标记。小鼠SPCs中E-cadherin的消耗对SPCs归巢和精子发生没有明显影响。
结果：这里，我们研究了E-cadherin在调节SPCs命运中的调节作用。E-cadherin在生殖细胞中的特异性缺失显示出促进SPCs分化,小鼠睾丸中PLZF+种群减少，c-Kit+种群增加。E-cadherin丢失下调β-catenin的表达水平，导致β-连环蛋白在核定位中的转录活性降低。值得注意的是,钙黏着蛋白-22（CDH22）表达水平的增加在E-钙黏着蛋白缺失后出现，表明CDH22与E-cadherin在SPCs中具有协同作用。通过寻找β-连环蛋白的结合伴侣，淋巴增强子结合因子1（LEF1），T细胞因子(TCF3),通过用PLZF调节分化基因的乙酰化，将组蛋白脱乙酰酶4（HDAC4）和信号转导和激活剂3（STAT3）鉴定为SPCs分化的抑制剂。
结论：SPCs的两个表面标记，E-cadherin和Cadherin-22通过关键的中间分子β-catenin协同维持SPCs的未分化。LEF1，TCF3，STAT3和HDAC4被鉴定为β-catenin调节SPC命运的共调节因子。这些观察结果揭示了钙黏着蛋白对SPCs命运的新调控模式。
结果：这里，我们研究了E-cadherin在调节SPCs命运中的调节作用。E-cadherin在生殖细胞中的特异性缺失显示出促进SPCs分化,小鼠睾丸中PLZF+种群减少，c-Kit+种群增加。E-cadherin丢失下调β-catenin的表达水平，导致β-连环蛋白在核定位中的转录活性降低。值得注意的是,钙黏着蛋白-22（CDH22）表达水平的增加在E-钙黏着蛋白缺失后出现，表明CDH22与E-cadherin在SPCs中具有协同作用。通过寻找β-连环蛋白的结合伴侣，淋巴增强子结合因子1（LEF1），T细胞因子(TCF3),通过用PLZF调节分化基因的乙酰化，将组蛋白脱乙酰酶4（HDAC4）和信号转导和激活剂3（STAT3）鉴定为SPCs分化的抑制剂。
结论：SPCs的两个表面标记，E-cadherin和Cadherin-22通过关键的中间分子β-catenin协同维持SPCs的未分化。LEF1，TCF3，STAT3和HDAC4被鉴定为β-catenin调节SPC命运的共调节因子。这些观察结果揭示了钙黏着蛋白对SPCs命运的新调控模式。
