Role of Glial-Cell-Line-Derived Neurotrophic Factor Signalling in Spermatogonial Stem Cells - Essay Example

Role of GDNF signalling in Spermatogonial Stem Cells Student’s Name Institution Affiliation Outline GDNF signalling is overly stipulated to play an essential role in spermatogonial stem cells renewal. This paper thus essentially seeks to review the much that has been done by researchers and scientists in examining the GDNF signalling. The first paragraph highlights the essentiality of the spermatogonial stem cells in the body in general. As posited by different scientific experiments, these cells are fundamental for the restoration of body tissues because of their unique ability to self renew. The second paragraph overly assesses the basic components that facilitate the ability of the spermatogonial stem cells to self renew. According to Kostereva & Hofmann (2008), the Sertoli cells, the basement of the membrane as well as the cellular components within the spermatogonial stem cells niche contribute largely in the enhancing the functions of the spermatogonial stem cells. The third and fourth paragraphs respectively look at the experiments that have been on mice as well as humans with respect to GDNF signalling. According to Spinnler et al. (2010) as well as Ruiz (2011), GDNF signalling is commonly originated from the testes of both mice and humans. In humans mostly, this essential cell reproduction component is exuded in vivo as well as in vitro. The subsequent paragraphs in this paper give the role of GDNF signalling in relevance to the reproduction of Spermatogonial stem cells. On the overall, GDNF signalling facilitates Spermatogonial stem cells proliferation, differentiation as well as DNA synthesis in Ret-expressing spermatogonia through basic pathways that are notably stimulated by various GDNF receptors. Role of GDNF signalling in Spermatogonial Stem Cells Stems cells are needed for the development, maintenance as well as restoration of tissues in the body. These body cells are commonly upheld for their ability to self renew. Their ability to self renew is attributed to the reception of relevant signals from the cells microenvironment usually referred to as the cell niche. Spermatogonial stem cells are mainly found in the mammalian testis. These cells are confirmed to be at the base membrane of testis and are scientifically considered to be in close contact with the Sertoli cells (Kostereva & Hofmann, 2008, p1). Kostereva and Hofmann (2008) assert that, the spermatogonial stem cells self restore to manage spermatogenesis all through the fully developed life of mature male animals. Additionally, these cells differentiate into different spermotogonia cells thus enhancing the quantity of germ cells in the body. Three essential components have been attributed as vital as far as the spermatogonial stem cells are involved; the Sertoli cells, the basement membrane as well as the cellular components found in the interstitial gap connecting the seminiferous tubules (Kostereva and Hofmann, 2008). The sertoli cells mainly offer growth factors, which are considered fundamental for self restoration. “Glial cell line-derived neurotrophic factor (GDNF)” is one of the most essential growth factor that has been linked with the ability of spermatogonial stem cells proliferation and differentiation. Research findings indicate that, the production of GDNF by the Sertoli cells is mainly through FGF2 as well as other mechanisms. Among these are “interleukin-1 beta and tumour necrosis factor alpha. Monocytes, macrophages as well as dendritic cells majorly generate the supplementary dynamics that contribute to GDNF synthesis by Sertoli cells (Kostereva & Hofmann, 2008, p4). Conversely, the basement membrane is looked upon as essential for offering anchorage while the cellular components are mainly well thought-out as fundamental for the localization of undifferentiated sprematogonia (p.1). A permutation of these basic components through signalling activates the self-restoration of the “spermatogonial stem cells”. GDNF signalling denotes the primary molecule that controls the cell outcome decision of the spermatogonial stem cells. In vivo, research findings reveal that GDNF signalling arbitrates the renewal as well as differentiation of undifferentiated spermatogonia. On the other hand, in experiments performed involving mice with limited GDNF, the findings revealed incomplete depletion of spermatogonial stem cells. Other experiments have also been performed to establish the role of GDNF signalling in Spermatogonial Stem Cells. Research reports indicate that GDNF signalling is fundamental factor in stem cell development (Ruiz, 2011, p15). In humans, GDNF signalling is majorly presumed to originate from the peritubular cells of the testis (Spinnler et al., 2010, p4). Considering the proximity of the GFR-α1 cells to the peritubular wall, The authors argue that the peritubular cells in humans have a vital role to play in cell restoration in the spermatogonial stem cells niche. These researchers acknowledge that the human peritubular cells express as well as exude GDNF in vivo as well as in vitro. Unlike the studies performed on mice at different ages, Spinnler et al. (2010, p.5) derived their cell samples from humans with “impaired spermatogenesis and testicular peritubular fibrotic remodelling”. The researchers established that the expression of GDNF signalling in these human cells was evident despite the condition of the spermatogenesis. However, they also assert that, the TNF-α and tryptase, which are commonly secreted by the immune cells and enhance the secretion of NGF by HTPCs did not have any impact on the role played by the peritubular wall cells in respect to the niche of stem cell and GDNF signalling. Spinnler et al. (2010) assert that, “GDNF- GFR-α1 structure is present in the human testis and engage testicular peritubular cells in their role regarding stem cell reproduction”. Spermatogonial stem cells (SSCs) are denoted to be crucial in the transmission of genetic characteristics from a male to its new generation. These cells (SSCs) are acknowledged to be the only stem cells in the body that are capable of renewing themselves through their cell life in addition to passing on genetic materials to new progenies (Jiang et al., 2008). The “Glial Cell Line-Derived Neurotrophic Factor (GDNF)” is presumed to control the proliferation of spermatogonial stem cells. This scientific presumption has initiated a number of experiments on mice by scientific scholars to assess the role of the GDNF signalling on the spermatogonial stem cells. Jiang et al (2008, p.1) observe that, the GDNF signalling when induced in a dosage manner, it has an impact on the spermatogonial stem cells. Overly, these scholars note that the GDNF signalling enables the renewal as well as differentiation of the spermatogonial stem cells. Kostereva and Hofmann (2008) concede that the spermatogonial stem cells exist in special microenvironments denoted as ‘niches’. This form of existence is acknowledged to facilitate the preservation as well as self-renewal of the stem cells. The unique feature of the spermatogonial stem cells of self-renewal is recognised to be essential for tissue homeostasis. The spermatogonial stem cells normally obtain fundamental signals from within their niche, which enable them to renew and effectively enhance tissue homeostasis. Kostereva and Hofmann (2008) point out that, GDNF signalling is basic requirement for self-renewal of the spermatogonial stem cells. They consider GDNF signalling as an essential protein synthesised by the Sertoli cells as well as being solely accountable for the maintenance as well as the “production of the spermatogonial stem cells in vivo and in vitro” (Kostereva & Hofmann, 2008, p.2). GDNF signalling is normally secreted by Sertoli cells. GDNF signalling usually works by binding itself to the “GFRα1 receptor as well as the GDNF- GFRα1 complex recruits tyrosine kinase receptor Ret for signalling” (Langsdorf et al., 2010). In addition, GDNF signalling also is noted to take part in enhancing the propagation of undifferentiated spermatogonial stem cells in vivo. Jiang et al. (2008) identify the guanosine triphosphatase protein Ras to be an essential mediator for proliferation as well as differentiation (p2). The extracellular signal-regulated kinases (ERK) is mostly considered as vital for c-kit expressing type A1-A4 spermatogonia which is majorly supported by the stem cell factor. Other scholars such as Xiaojuan et al., (2000) note that, GDNF signalling is a member of the change development factor-β. In this, it is posited to enhance the survival of as well as differentiation of a number of neurons in the nervous system (p.2). More often than not, GDNF signalling is considered to be effective in enhancing Sertoli cell proliferation in vitro. In an in vivo experiment performed by Xiaojuan et al. (2000) to assess the in vivo operation of GDNF signalling in spermatogenesis, “gene-targeted mice with declining and elevated GDNF expressions were used” (p2). The findings revealed that a number of the GDNF mice continued to exist to their adulthood and managed to retain their fertility. An analysis into the histology of their testes disclosed that the spermatogenesis of the mice had been tampered with (Fu et al., 2011, p5). Findings from research experiments performed on mice to explore the renewal as well as differentiation of spermatogonial stem cells have only been acquired recently. Mice that are 3 years of age are acknowledged to over express the GDNF signalling group factor. In most cases, mice at this age are acknowledged to reveal the presence of single A spermatogonia. At subsequent ages, these GDNF signalling factors (A spermatogonia) fade away. However, studies reveal that, the tubules of the testis grow to be lined with the single A spermatogonia which take up the place of the left over normal spermatogenesis. In addition to this, at an older age of 1 year, these mice were reported to have germ cell tumours in their testis. From these findings, Rooij (2001) asserts that GDNF signalling encourages stem cell reproduction. On the other hand, for some mice that did not indicate the presence of germ cells, Rooij posits that the stem cells of these mice are being depleted, an indication that supports the role of GDNF signalling in spermatogonial stem cells reproduction (Virtanen, 2009). The presence of the GDNF signalling factor in the mice overly suggests that by expressing more or limited GDNF, the Sertoli cells are able to control the duplicate of spermatogonial stem cells (Rooij, 2001, p.4). In a study conducted by Dovere et al. (2013), it was established that GDNF signalling stimulates directional migration of undifferentiated spermatogonia. An experiment was performed involving immature mice where the scientists obtained spermatogonial stem cells from the mice and cultured them under a specific routine. A considerable figure of the spermatogonial stem cells derived were noted to move about on the introduction of GDNF. This seeming outcome revealed that “in vitro GDNF signalling could trigger directional movement of undifferentiated spermatogonial stem cells” (Planken, 2012). In this experiment, it is apparent that GDNF signalling influences seminoma cell movement via the Src as well as MEK pathways. In this study, the researchers report that, GFRA, which is a common co-receptor for GDNF signalling, is usually over expressed in humans’ in situ carcinoma as well as in the intra-tubular and invasive seminoma (Dovere et al., 2013, p.6). This co-receptor triggers cell migration through Src and MEK pathways. GDNF signalling is exposed to heparin sulphates and stimulates Src, which eventually leads to cell adhesion, as well as spreading (Dovere et al., 2013, p7). The figure below described the signalling of GDNF/Ras in “spermatogonial stem cells” (Hoffman, 2008). In a research conducted by Jiang et al. (2008), to determine the signalling of GDNF via Ras/ERK1/2 pathways, the researchers established that GDNF signalling sets in motion the tyrosine phosphorylation of Ret and Shc. Additionally, GDNF signalling initiated the joining of the phosphorylated Ret to Shc as well as Grb2, which eventually triggers the Ras/ERK1/2 pathway (Fig above). The pathway then resulted in “the phosphorylation of the transcription factors cAMP responsive element binding protein one (CREB-1), the activating transcription factor-1 (ATF-1) as well as the cAMP response element modulation protein one (CREM-1) and the transcription of the immediate early gene c-fos” (Jiang et al., 2008, p2). Langsdorf et al. (2010) suggest that GDNF signalling is highly supported by Sulfs. These scholars acknowledge that Sulfs controls the bioavailability of GDNF signalling through enzymatic changing of HS 6-O-desulfation, which triggers the discharge of GDNF signalling (Jiang et al., 2008). GDNF signalling also take part in the stimulation of DNA synthesis in Ret-expressing spermatogonia. GDNF signals throughout a multi-component receptor complex consisting of the “Ret receptor tyrosine kinase and a member of the GFR_ family of glycosylphosphatidylinositol (GPI) anchored receptors, which are essential for GDNF binding to Ret” (Jiang et al., 2008). In the nervous tissue, numerous pathways are explained for GDNF signaling. GDNF signalling can trigger intracellular signaling through a Ret-independent pathway via GPI-linked protein GFR_1, which leads to activation of Src family tyrosine kinase and mediates various downstream responses to promote cell survival (Jiang et al., 2008). Jiang et al. (2008) performed an experiment to examine the role of GDNF signalling in stimulating DNA synthesis in Ret-expressing spermatogonia. According to their findings, they noted that, GNDF stimulation facilitated the activation of the Ret phosphorylation at tyrosine 1,062 in the C18-4 cells (Jiang et al., 2008, p.10). This activation is usually acknowledged essential for the establishment of the Ras/ERK pathway, which essentially stirs up DNA synthesis (Yang, 2006). GDNF signalling also aids the expansion of “spermatogonial stem cells” over an extended culture period. Scientifically, GDNF signalling has been considered essential for postnatal spermatogenesis. In a study performed by Wan and Too (2010) to assess cell elongation with respect to their ability to migrate, the researchers found out that the C6 cells overly express as well as secrete GDNF at elevated levels (p.9). The C6 cells are commonly acknowledged highly migratory even when they are not roused through stimulations like the introduction of induced GDNF signalling. The ability of the C6 cells to elongate was established as possible following the knockdown of GFR-α1b (Jiang et al., 2008). Proper maintenance of the “spermatogonial stem cells” is posited to be essential for progressive male fertility. GDNF signalling via the RET/GDNF receptor GFR-α1 has been perceived to be the most fundamental for the reproduction of the “spermatogonial stem cells”. Jijiwa et al. (2008) examined the impact of signalling through RET tyrosine 1062 in spermatogenesis. The researchers adapted mice as their study subjects. In this study, the researchers substituted the tyrosine 1062 with phenylalanine. The findings of the study revealed that, when phosphorylated, the tyrosine 1062 in the receptor cells of GDNF signalling provide a joining site for a number of adaptor as well as effectors proteins which are considered to be essential for the trigger of intercellular signalling pathways (Jijiwa et al., 2008, p1). The mice in the study revealed that homozygous Y1062F mice had minimal levels of germ cells. This indication posited that there was condensed production of RET expressing spermatogonia in the mice after birth. Essentially, this revealed that there was no reproduction of the “spermatogonial stem cells” and hence, the incapability of the cells to sustain their undifferentiated condition. These findings clearly reveal the essentiality of GDNF signalling through the RET receptor via tyrosine 1062 to be fundamental for the reproduction of the spermatogonial stem cells (Jijiwa et al., 2008). In essence, RET receptor factor is usually expressed with GFR-α1 a co-factor of the GDNF signalling family. These basic components of GDNF signalling are mainly situated in the germ cells, which are considered to be linked to spermatogonia stem cells; the gonocyte which represents the preliminary germ cell of spermatogenesis and the undifferentiated spermatogonium. After birth, the genocytes normally move to the interior of the seminiferous tubules. Subsequently, these cells migrate to the basement membrane of the testes where they eventually differentiate into type A spermatogonia which are commonly referred to as spermatogonia stem cells. With respect to the different studies performed by the researchers acknowledged in this study, it is evident that GDNF signalling influences the spermatogonia stem cells (Alfano & Mulloy, 2007, p.25). At minimal levels of GDNF, spermatogonia is considered to have a preference for cell differentiation whereas at an elevated level it prefers self renewal (Jijiwa et al., 2008, p7). Numerous studies have been conducted to identify the role of GDNF signalling in spermatogonia stem cells. Up until recently, several factors obtained from testicular somatic cells have been examined to reveal their impact on “spermatogonia stem cells” renewal. Tests as well as experiments have been performed on Sertoli cells as well as the peritubular cells. Yeh et al. (2012) further acknowledges that Wnt3a also influences the “differentiation as well as cell self-renewal of the spermatogonia stem cells”. According to these researchers, Wnt signalling plays a vital role in the “spermatogonia stem cells” niches. This signalling is conceded to trigger the β catenin pathway, which essentially increases the cell number of the spermatogonia stem cells. The “spermatogonia stem cells” increase in number following an indirect stimulation of the formation of cluster communities in their niche (Yeh et al., 2012, p6). GDNF signalling triggers cell cycle development in spermatogonia stem cells through its ability to initiate DNA synthesis, cell proliferation as well as cell differentiation through different signalling pathways (Laslett, et al., 2007). A number of studies have been done quantitatively to examine the extent of the GDNF signalling in spermatogonia stem cells reproduction. Evidently, there are numerous evidences in as far as the GDNF signalling influences spermatogonia stem cells reproduction in mice, humans as well as horses. The apparent evidence of the ability of the spermatogonia stem cells to transfer genetic components from one generation to another has also been made apparent through these different studies by the researchers mentioned in the body of this study. GDNF signalling evidently influences the behaviour of the spermatogonia stem cells in their respective niches by transmitting microenvironmental signals, which trigger the cells to self, renew, proliferate as well as increase in numbers. In summary, it is thus prudent to state that GDNF signalling in its various signalling forms influences the reproduction, DNA synthesis as well as differentiation of spermatogonia stem cells. 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