Table 1.
Sertoli cell-derived factors that regulate FLC progenitor formation and FLC differentiation.
| Factor symbol | Full name of factor | Function |
|---|---|---|
| Promoting factors KITL | KIT ligand, also known as stem cell factor, SCF | Blockade of KITL/KIT (KIT oncogene, also known as c-KIT, a protein tyrosine kinase) pathway in ethylene dimethane sulfonate (EDS)-induced ALC depletion in rat testes accelerates ALC apoptosis and inhibits ALC progenitor proliferation, suggesting that KITL/KIT signaling is involved in ALC survival and ALC progenitor growth [57]. Since KIT is also expressed by FLCs [58], it is likely that the KITL/KIT signaling is crucial to FLC development. |
| DHH | Desert Hedgehog | In Dhh knockout mouse, FLC number is down-regulated without changes in FLC progenitor migration and survival, while ectopically activation of Hedgehog pathway in fetal ovaries results in the transformation of ovarian somatic cells to functional FLCs, indicating DHH/PTCH1 (Patched 1, the receptor of DHH) signal pathway triggers FLC differentiation [59,60]. |
| PDGFα | Platelet-derived growth factor A | Pdgfrα (Platelet-derived growth factor receptor A, the receptor of PDGFα) deletion in fetal mouse leads to defects in mesonephric cell migration and down-regulation of FLC marker expression, indicating that PDGFα/PDGFRα signal pathway is involved in FLC progenitor migration and FLC differentiation [24]. |
| Inhibiting factors | ||
| AMH | Ati-Müllerian hormone, also known as Müllerian inhibiting substance (MIS) or factor (MIF) | AMH inhibits androgen production by dispersed rat FLCs in culture in a dose-dependent manner without affecting FLC number [61], suggesting that AMH serves as a negative modulator of FLC function. |
| WT1 | Wilms’ tumor 1 | Specific inactivation of Wt1 in Sertoli cells in fetal mouse testes using Wt1−/flox; Amh-Cre mice has shown that ALCs fail to replace FLCs in these mutant testes in adult mice, and FLCs remain mitotically active from postnatal day 1 to day 56 [8] through the NOTCH-mediated signaling pathway [62]. Thus, the WT1-NOTCH signaling plays an important role in modulating FLC differentiation during fetal, neonatal and postnatal testis development. |
| miR-140-3p/5p | microRNA miR-140-3p/5p | Analysis of the miR-140-3p/5p-null mouse revealed a significant increase in the number of FLCs in fetal testes and the predicted targeted genes regulated by canonical miR-140-3p/5p are associated with NOTCH signal pathway, suggesting an important role for Sertoli cell miR-140-3p/5p in FLC differentiation via NOTCH signal pathway [63]. |