Abstract
In mammals, spermatogonial stem cells (SSCs) arise from early germ cells called gonocytes, which are derived from primordial germ cells during embryogenesis and remain quiescent until birth. After birth, these germ cells migrate from the center of testicular cord, through Sertoli cells, and toward the basement membrane to form the SSC pool and establish the SSC niche architecture. However, molecular mechanisms underlying germ cell migration and niche establishment are largely unknown. Here, we show that the actin disassembly factor actin interacting protein 1 (AIP1) is required in both germ cells and Sertoli cells to regulate this process. Germ cell-specific or Sertoli cell-specific deletion of Aip1 gene each led to significant defects in germ cell migration after postnatal day 4 or 5, accompanied by elevated levels of actin filaments (F-actin) in the affected cells. Furthermore, our data demonstrated that interaction between germ cells and Sertoli cells, likely through E-cadherin-mediated cell adhesion, is critical for germ cells' migration toward the basement membrane. At last, Aip1 deletion in Sertoli cells decreased SSC self-renewal, increased spermatogonial differentiation, but did not affect the expression and secretion levels of growth factors, suggesting that the disruption of SSC function results from architectural changes in the postnatal niche.
Highlights
In neonatal mice, germ cells express the cell adhesion molecule E-cadherin on the cell surface,[10,11] whereas other adhesion markers including N-cadherin and β1-integrin were found in both germ cells and Sertoli cells.[12,13,14] whether these adhesion molecules have specific roles in germ cells’ outward migration and subsequent differentiation were not yet known
To obtain germ cell-specific Aip[1] knockout, we crossed Aip1fl/fl with Vasa-cre mice that express cre in the germline beginning from embryonic day 15 (E15).28 Western blot analysis of THY1+ germ cells extracted from testes of postnatal day 7 (P7) Aip1fl/−: Vasa+/cre mice showed an almost complete removal of the actin interacting protein 1 (AIP1) protein, indicating an efficient deletion of Aip[1] in the germ cells (Figure 1a)
spermatogonial stem cells (SSCs)’s migration, in the context of homing to the germline niche, has recently been extensively studied. This migration event requires RAC1 and β1-integrin, but not E-cadherin in the spermatogonia, and it requires β1-integrin in the Sertoli cells.[13,53]
Summary
Germ cells express the cell adhesion molecule E-cadherin on the cell surface,[10,11] whereas other adhesion markers including N-cadherin and β1-integrin were found in both germ cells and Sertoli cells.[12,13,14] whether these adhesion molecules have specific roles in germ cells’ outward migration and subsequent differentiation were not yet known. Received 23.10.14; revised 18.5.15; accepted 19.5.15; Edited by M Agostini is consistent with findings in other systems that dynamics of actin cytoskeleton directly regulate the assembly and maintenance of E-cadherin-based cell adhesion.[17] Interestingly, we have previously shown that actin interacting protein 1 (AIP1), an actin disassembly factor, regulates E-cadherin distribution and dynamics during a cell rearrangement process of the Drosophila eye disc.[18] AIP1 has been shown to act together with cofilin/actin-depolymerizing factors to promote actin dynamics in various cellular processes, and it is highly conserved in all eukaryotes examined so far.[19,20,21,22,23,24] Here, we utilized germ cell- or Sertoli cell-specific deletion of Aip[1] ( known as Wdr1) in the murine testis to study the process of germ cell migration and SSC niche establishment
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