TGM6转基因小鼠模型的构建和鉴定
摘要
脊髓小脑型共济失调(spinocerebellar ataxia, SCA)是一种具有高度临床和遗传异质性的神经系统退行性疾病,多呈常染色体显性遗传。随着分子遗传学的研究进展,陆续鉴定出新的致病基因。到目前已发现了33个不同的基因亚型,其中23个亚型的致病基因已被克隆出来。2010年,我们实验室应用Exome sequencing技术在两个无关的常染色体显性遗传家系中发现两个不同位置的突变：TGM6基因10号外显子的c.1550T-G(L517W)突变和7号外显子c.980A-G (D327G)突变。从而鉴定出一个新的SCA致病基因TGM6,该SCA新亚型被人类基因命名委员会正式命名为SCA35。
SCA各亚型致病基因的分子发病机制并不完全一样。TGM6基因本身的生物学功能目前国内外尚无研究报道。为了探讨TGM6的基本生物学功能以及突变引起SCA35的发病机制,我们构建两种突变型和野生型TGM6基因的转基因小鼠模型,使小鼠表达人类突变和野生的TG6蛋白。此外,目前缺乏TGM6基因在中枢神经系统内的细胞水平表达谱的资料,而这些资料对于了解其功能是必需的。因此,本论文采用免疫组化方法调查了TGM6基因在中枢神经系统内的分布情况及其阳性神经元的化学神经解剖学特征。
为了构建携带人类L517W突变、D327G突变和野生型TGM6基因的转基因小鼠模型,首先构建了pCAGGS-TGM6wt-Myc-GFP、 pCAGGS-TGM6L517W-Myc-GFP和pCAGGS-TGM6D327G-Myc-GFP三个转基因表达载体。转基因表达载体上带了Myc和GFP两个标签。这些载体在培养细胞进行了验证。
在此基础上,我们制备了以上表达人TGM6的三种转基因小鼠：即L517W突变、D327G突变和野生型TGM6。以上小鼠通过PCR和测序验证。应用Western Blot检测GFP和Myc,在蛋白水平证实了转基因的表达。通过TG6和GFP(或Myc)免疫双重染色,在细胞水平显示转基因TG6确实表达于中枢神经系统内。转基因小鼠的成功制备,为后续在整体动物水平研究TGM6及其突变体的功能提供了工具。
TGM6在野生型小鼠中枢神经系统表达模式的研究发现,TG6蛋白主要表达在小鼠的间脑、脑干和小脑,表达在神经元而非神经胶质细胞。TG6阳性细胞主要分布在包括苍白球、底丘脑核、黑质、小脑等与运动调节功能密切的脑区。在黑质网状部,TG6主要表达在抑制性的GABA能神经元中。
The spinocerebellar ataxias (SCAs) are a heterogeneous group of inherited neurodegenerative disorders. To date, classical genetic studies have revealed33distinct genetic forms of spinocerebellar ataxias, and23causative genes have been cloned. In2010, our group identified two missense mutations in the TGM6gene in two Chinese SCA families, c.1550T>G transition (p.L517W) and c.980A>G transition (p.D327G), suggesting a novel causative gene for SCA, which has been named as SCA35.
The molecular pathogenesis among the SCA subtypes may be different. To explore the mechanism of SCA35and the function of TGM6, we generate the transgenic mice carrying the L517W and D327G mutation and wild-type of human TGM6gene. In addition, there has been no report concerning the cellular distribution of TG6in the adult brain, we thus set out to investigate TGM6gene expression in the central nervous system. This data is the basis for further dissecting the physiological function of TGM6.
The molecular pathogenesis of the SCA subtypes may be different. There isn't the report about the physiological function of TGM6gene at home and abroad. To explore the function of TGM6and the mechanism of SCA35, we construct the transgenic mice which carry the L517W and D327G mutation and wild-type of human TGM6gene. In addition, there is few data about TGM6gene expression patterns in the central nervous system. These data is necessary to learn the function of TGM6. Therefore, the thesis investigated the expression patterns in the central nervous system of TGM6and the chemical neuroanatomical characteristics of positive neurons.
To generate transgenic mice carrying the mutations of L517W and D327G, and wild-type human TGM6gene, we constructed pCAGGS-TGM6wt-Myc-GFP, pCAGGS-TGM6L517W-Myc-GFP and pCAGGS-TGM6D327G-Myc-GFP transgenic expression vectors, with Myc and GFP tag. These vectors expressed the transgenes effectively in eukaryocytes.
The three transgenesic mice expressing human TGM6mutations of L517W and D327G, and the wild-type TGM6were obtained. The three transgenic mice were confirmed by PCR and sequencing, and by detecting expression of GFP and Myc with Western blot, which indicated the expression of transgenes at the protein level. In addition, to show expression of transgenes at the cellular level, we performed double immunological staining of TG6with GFP (or Myc). It showed that TG6immunoreactivity was co-localized with GFP or Myc in the brain. Thus, we have made the transgenic mice carrying human TGM6(wild type and two mutations), which provided a good tool for investigating the function of human TG6in vivo.
Immunohistochemistry of TG6in adult brains showed that TG6was abundantly expressed in the diencephalon, brainstem and cerebellum. TG6was located in neurons but not glia cells. Notably, numerous TG6-positive neurons were distributed in the key brain regions involved in regulating locomotion activity including the globus pallidus, subthalamic nucleus, substantia nigra and cerebellum. In addition, we found that the vast majority of TG6-positive cells in the reticular part of substantia nigra were GABAergic inhibitory neurons.
SCA各亚型致病基因的分子发病机制并不完全一样。TGM6基因本身的生物学功能目前国内外尚无研究报道。为了探讨TGM6的基本生物学功能以及突变引起SCA35的发病机制,我们构建两种突变型和野生型TGM6基因的转基因小鼠模型,使小鼠表达人类突变和野生的TG6蛋白。此外,目前缺乏TGM6基因在中枢神经系统内的细胞水平表达谱的资料,而这些资料对于了解其功能是必需的。因此,本论文采用免疫组化方法调查了TGM6基因在中枢神经系统内的分布情况及其阳性神经元的化学神经解剖学特征。
为了构建携带人类L517W突变、D327G突变和野生型TGM6基因的转基因小鼠模型,首先构建了pCAGGS-TGM6wt-Myc-GFP、 pCAGGS-TGM6L517W-Myc-GFP和pCAGGS-TGM6D327G-Myc-GFP三个转基因表达载体。转基因表达载体上带了Myc和GFP两个标签。这些载体在培养细胞进行了验证。
在此基础上,我们制备了以上表达人TGM6的三种转基因小鼠：即L517W突变、D327G突变和野生型TGM6。以上小鼠通过PCR和测序验证。应用Western Blot检测GFP和Myc,在蛋白水平证实了转基因的表达。通过TG6和GFP(或Myc)免疫双重染色,在细胞水平显示转基因TG6确实表达于中枢神经系统内。转基因小鼠的成功制备,为后续在整体动物水平研究TGM6及其突变体的功能提供了工具。
TGM6在野生型小鼠中枢神经系统表达模式的研究发现,TG6蛋白主要表达在小鼠的间脑、脑干和小脑,表达在神经元而非神经胶质细胞。TG6阳性细胞主要分布在包括苍白球、底丘脑核、黑质、小脑等与运动调节功能密切的脑区。在黑质网状部,TG6主要表达在抑制性的GABA能神经元中。
The spinocerebellar ataxias (SCAs) are a heterogeneous group of inherited neurodegenerative disorders. To date, classical genetic studies have revealed33distinct genetic forms of spinocerebellar ataxias, and23causative genes have been cloned. In2010, our group identified two missense mutations in the TGM6gene in two Chinese SCA families, c.1550T>G transition (p.L517W) and c.980A>G transition (p.D327G), suggesting a novel causative gene for SCA, which has been named as SCA35.
The molecular pathogenesis among the SCA subtypes may be different. To explore the mechanism of SCA35and the function of TGM6, we generate the transgenic mice carrying the L517W and D327G mutation and wild-type of human TGM6gene. In addition, there has been no report concerning the cellular distribution of TG6in the adult brain, we thus set out to investigate TGM6gene expression in the central nervous system. This data is the basis for further dissecting the physiological function of TGM6.
The molecular pathogenesis of the SCA subtypes may be different. There isn't the report about the physiological function of TGM6gene at home and abroad. To explore the function of TGM6and the mechanism of SCA35, we construct the transgenic mice which carry the L517W and D327G mutation and wild-type of human TGM6gene. In addition, there is few data about TGM6gene expression patterns in the central nervous system. These data is necessary to learn the function of TGM6. Therefore, the thesis investigated the expression patterns in the central nervous system of TGM6and the chemical neuroanatomical characteristics of positive neurons.
To generate transgenic mice carrying the mutations of L517W and D327G, and wild-type human TGM6gene, we constructed pCAGGS-TGM6wt-Myc-GFP, pCAGGS-TGM6L517W-Myc-GFP and pCAGGS-TGM6D327G-Myc-GFP transgenic expression vectors, with Myc and GFP tag. These vectors expressed the transgenes effectively in eukaryocytes.
The three transgenesic mice expressing human TGM6mutations of L517W and D327G, and the wild-type TGM6were obtained. The three transgenic mice were confirmed by PCR and sequencing, and by detecting expression of GFP and Myc with Western blot, which indicated the expression of transgenes at the protein level. In addition, to show expression of transgenes at the cellular level, we performed double immunological staining of TG6with GFP (or Myc). It showed that TG6immunoreactivity was co-localized with GFP or Myc in the brain. Thus, we have made the transgenic mice carrying human TGM6(wild type and two mutations), which provided a good tool for investigating the function of human TG6in vivo.
Immunohistochemistry of TG6in adult brains showed that TG6was abundantly expressed in the diencephalon, brainstem and cerebellum. TG6was located in neurons but not glia cells. Notably, numerous TG6-positive neurons were distributed in the key brain regions involved in regulating locomotion activity including the globus pallidus, subthalamic nucleus, substantia nigra and cerebellum. In addition, we found that the vast majority of TG6-positive cells in the reticular part of substantia nigra were GABAergic inhibitory neurons.
引文
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