Matrix metalloproteinase-dependent regulation of extracellular matrix shapes the structure of sexually differentiating mouse gonads

Abstract

To cite this version:Rafal P. Piprek, Malgorzata Kloc, Jacek Z. Kubiak. Matrix metalloproteinase-dependent regulation of extracellular matrix shapes the structure of sexually differentiating mouse gonads. Differentiation, Elsevier, 2019, 106, pp. Abstract 35The extracellular matrix (ECM) proteins play an important role in the establishment of 36 the sex-dependent structure of developing gonads. The matrix metalloproteinases (MMPs) are 37 the major players in the regulation of ECM. Our hypothesis was that the MMPs-dependent 38 regulation of EMC is crucial for the establishment of the correct, either testis or ovary, 39 structure of developing gonad. We cultured developing mouse gonads in vitro in the presence 40 of the MMPs inhibitors (α-2-macroglobulin, leupeptin, phosphoramidon) or the MMPs 41 activator, APMA (4-aminophenylmercuric acetate). These inhibitors and activator 42 inhibit/activate, to a different degree, matrix metalloproteinases, but the exact mechanism of 43 inhibition/activation remains unknown. We found that the MMP inhibitors increased 44 accumulation of ECM in the developing gonads. The α-2-macroglobulin had the weakest, and 45 the phosphoramidon the strongest effect on the ECM and the structure of the gonads. The α-2-46 macroglobulin caused a slight increase of ECM and did not disrupt the gonad structure. 47 65 macroglobulin; leupeptin; phosphoramidon; APMA 67 68 2001), the elongated cords do not develop. The ovigerous cords are built of many small and 94 irregularly shaped clusters of the somatic and germ cells, known as the germ cell nests, 95 embedded in the ovarian stroma (Lei and Spradling, 2013). Later in development, the 96 ovigerous cords split into ovarian follicles (Pepling and Spradling, 2001;Pepling et al., 2010). 97It has been shown that in mouse, rat, cattle, chicken, slider (Trachemys scripta) and the 98 African clawed frog (Xenopus laevis) (Paranko et al., 1983;Yao et al., 2004; Hummitzsch et 99 al., 2013;Piprek et al., 2017aPiprek et al., ,2018 the ECM plays important role in gonad development. The 100 ECM contains many different proteins including collagens, laminins, fibronectin, and 101 proteoglycans (reviewed by Yue, 2014). The amount and distribution of ECM depends on two 102Because the ECM is differentially patterned in developing testes and ovaries, and the 131 genes encoding ECM components and enzymes responsible for ECM remodeling are 132 differentially expressed, we hypothesized that the ECM and its enzymes are important factors 133 controlling sexual differentiation of the gonads. The aim of this study was to explore how the 134 structure of differentiating mouse testes and ovaries changes upon inhibition or activation of 135 ECM regulating enzymes. Fetal gonads isolated at E11.5, i.e. just before the onset of sexual 136

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