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Gsdma3基因在毛囊分化过程中的作用及机制探讨

发布时间:2018-10-31 17:06
【摘要】:毛囊是具有周期性生长特征的、复杂的微器官。在胚胎发育时期,毛囊起始于表皮细胞和间充质细胞的相互作用。当上皮细胞向下增殖并进入真皮时,毛母质细胞会包绕作为主要信号源的真皮乳头细胞,并且增殖分化为具有多层结构的内根鞘和毛干。其中内根鞘由亨勒层,郝胥黎层和鞘小皮组成。毛干也由三层结构组成,依次为毛小皮,皮质和髓质。毛干最内层的角质层与内根鞘的角质层相互咬合,形成一种锚定结构。这种结构能够有效地防止毛干的脱落。毛囊分化的调控涉及多条信号通路,包括Bmp,homeobox基因以及Wnt。这些信号在真皮乳头或毛母质细胞中的特异性表达决定了它们在分化中的作用。然而,人们对于其中涉及的细胞和分子机制仍然知之甚少。 Gsdma3基因是近年来新发现的小鼠基因,被认为是一个突变热点。之前的研究认为,作为一个突变位点,Gsdma3的突变会导致小鼠产生脱毛以及过度角化的表型。已有研究都显示了Gsdma3在毛囊维持上起着重要作用。然而,为什么Gsdma3突变鼠会脱毛,其中又涉及了哪些调控机制,对于这些问题我们还不清楚。先前的研究分别通过原位杂交和免疫组织化学显示了Gsdma3 mRNA和蛋白的表达,但结果却并不一致。 为了查证Gsdma3的缺失是如何导致毛发缺陷的,我们把一种新的Gsmda3突变鼠作为我们的实验模型。在这些突变鼠中,外部毛发变短并且参差不齐。在出生后25天,小鼠就开始从头部区域开始脱毛,直至整个背部。但是,当一个新的毛囊周期开始时,毛发也会重新生长。这个过程伴随渐进性的毛发脱落和生长。超微结构和组织学分析显示,该突变鼠的毛发结构异常,角蛋白表达减少。锚定结构的丢失和异常的结构蛋白表达都提示了毛发不能锚定在毛囊中,并且难以抵抗外力。因此,Gsdma3的功能缺失会使内根鞘和毛干结构分化异常。我们用免疫组织化学检测了Gsdma3表达于毛母质,内根鞘以及毛干,而这些细胞类型都与毛囊分化密切相关。Gsdma3缺陷的分子分析显示,Msx2调控通路的主要调控子在突变鼠中显著下调。并且Gsdma3与Msx2的表达部位一致。当我们通过皮下质粒注射过表达Gsdma3的时候,所有这些基因的表达又会上调。这些结果显示了Gsdma3可能直接或间接调控Msx2信号通路。总之,我们的结果提示Gsdma3对于毛囊分化至关重要,且可能是通过调控Msx2/Foxn1/acidic hair keratin信号级联来起作用的。
[Abstract]:Hair follicles are complex microorgans characterized by periodic growth. During embryonic development, hair follicles begin with the interaction of epidermal cells and mesenchymal cells. When the epithelial cells proliferate downward and enter the dermis, the dermal papilla cells, which are the main signal sources, will be wrapped around the hair mother cells, and they will proliferate and differentiate into the inner root sheath and the hair stem with multilayer structure. The inner root sheath consists of Henley layer, Huxley layer and sheath skin. The hair stem is also composed of three layers, which are the trichomes, cortex and medulla. The cuticle of the innermost layer of the hair stem bites with the cuticle of the inner root sheath to form an anchor structure. This structure can effectively prevent the hair from falling off. Regulation of hair follicle differentiation involves multiple signaling pathways, including Bmp,homeobox gene and Wnt. The specific expression of these signals in dermal papilla or dermal mother cells determines their role in differentiation. However, little is known about the cellular and molecular mechanisms involved. Gsdma3 gene is a newly discovered mouse gene in recent years, which is considered to be a hot spot of mutation. Previous studies have suggested that mutations in Gsdma3, as a mutation site, lead to hair loss and hyperkeratosis in mice. Previous studies have shown that Gsdma3 plays an important role in hair follicle maintenance. However, it is not clear why Gsdma3 mutant mice lose hair and what regulatory mechanisms are involved. Previous studies showed the expression of Gsdma3 mRNA and protein by in situ hybridization and immunohistochemistry, but the results were not consistent. In order to find out how the loss of Gsdma3 leads to hair defects, we used a new Gsmda3 mutant mouse as our experimental model. In these mutant mice, the outer hair is shorter and uneven. At 25 days after birth, the mouse began hair removal from the head area to the entire back. However, when a new hair follicle cycle begins, the hair also grows again. This process is accompanied by progressive hair loss and growth. Ultrastructural and histological analysis showed that the hair structure of the mutant mouse was abnormal and the expression of keratin decreased. Loss of anchoring structure and abnormal expression of structural protein indicate that hair can not be anchored in hair follicles and can not resist external force. Therefore, the absence of Gsdma3 function may cause abnormal differentiation of inner root sheath and hairy stem structure. We used immunohistochemistry to detect the expression of Gsdma3 in hair matrix, inner root sheath and hair stem, and these cell types were closely related to hair follicle differentiation. The main regulators of the Msx2 regulatory pathway were significantly down-regulated in mutant mice. The expression of Gsdma3 and Msx2 were consistent. When we express Gsdma3 subcutaneously, all these genes are up-regulated. These results suggest that Gsdma3 may directly or indirectly regulate the Msx2 signaling pathway. In conclusion, our results suggest that Gsdma3 is essential for hair follicle differentiation and may function by regulating Msx2/Foxn1/acidic hair keratin signaling cascades.
【学位授予单位】:重庆大学
【学位级别】:硕士
【学位授予年份】:2011
【分类号】:R751

【参考文献】

相关期刊论文 前1条

1 孙乔;张令强;贺福初;;GSDMDC家族的基因功能[J];遗传;2006年05期



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