HSP22转基因小鼠模型的建立
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摘要
腓骨肌萎缩症(Charcot-Marie-Tooth disease,CMT)又称为遗传性运动感觉性神经病(Hereditary Motor and Sensory Neuropathy,HMSN),是最常见的遗传性周围神经病,具有高度的临床和遗传异质性,临床上以肢体远端肌肉进行性对称性的萎缩、无力、腱反射减弱和感觉减退等为主要特征,发病率约为1/2500。根据电生理和病理学特点,CMT可分为脱髓鞘型(CMT1)和轴索型(CMT2),根据遗传方式的不同,CMT可呈常染色体显性遗传(AD)、常染色体隐性遗传(AR)和X连锁遗传(XD/XR)。随着分子遗传学的发展,迄今为止,腓骨肌萎缩症的基因型己达32型,其中22型已克隆。2004年,我们将一个来自中国湖南和湖北的常染色体显性遗传的CMT2型大家系定位在12q24.2-12q24.3之间的6.8cM区域,命名为CMT2L型(OMIM号608673),随后通过候选基因克隆策略,在该定位区间发现了小分子热休克蛋白22基因(Small heat shock protein 22,HSP22)的423G→T错义突变,导致氨基酸K141N的替换,与该CMT2L型家系的疾病表型共分离,从而证实HSP22为CMT2L型的致病基因。
研究表明,CMT各亚型致病基因的分子发病机制并不完全一样,可能通过致病基因的剂量效应、功能丧失、功能获得或显性-负性作用而致病。国外研究表明,HSP22与HSP27存在蛋白-蛋白相互作用,而且还发现,HSP22可能与调节HSP27的活性有关,HSP22基因的K141N突变后并没有破坏其编码蛋白与HSP27的相互作用,相反,这种相互作用还增强了并且导致蛋白聚集物的形成,表明K141N突变可能是通过功能获得作用而致病。为了证实上述推测,我们拟应用微纤维注射技术构建HSP22基因K141N的转基因小鼠模型,使小鼠携带人类突变的HSP22蛋白,验证该突变的功能获得作用。
最近的研究发现,HSP27突变后也可引起CMT,HSP22和HSP27基因突变可以引起同样的疾病表型,这无疑为CMT发病机制的相关性研究提供了一个很好的线索和思路。通过对HSP27过表达转基因小鼠模型进行研究,发现HSP27不仅对癫痫后的病理改变、心肌缺血和脑缺血之后的再灌注损伤都有保护作用,而且对神经损伤修复、肌肉功能的维持也有重要作用。HSP22是否具有同样的功能,目前国内外尚无系列的研究报道,也无关于HSP22的过表达转基因小鼠构建的报道。因此,为了更好的研究HSP22基因的功能及该基因突变后的分子致病机制,构建HSP22的过表达转基因小鼠模型是非常必要的。
为了构建携带人类HSP22基因K141N突变和野生型HSP22基因的转基因小鼠模型,我们成功构建了pCAGGS-HA-~(K141N)HSP22和pCAGGS-HA-~(wt)HSP22两个转基因表达载体。通过激光共聚焦显微镜和Western Blot分析,证实了pCAGGS-HA-~(K141N)HSP22和pCAGGS-HA-~(wt)HSP22可在真核细胞有效表达,并验证了K141N突变型HSP22在活体外细胞系中形成以核周分布为主的聚合物,野生型HSP22在活体外细胞系中弥散分布于胞浆和胞核内。应用HA单克隆抗体,可以特异性检测出约25.5kDa大小的带HA-tag的HSP22蛋白。体外实验证实pCAGGS-HA-~(K141N)HSP22和pCAGGS-HA-~(wt)HSP22能用于转基因小鼠的构建后,我们用SalⅠ、HindⅢ和BsaⅪ三个核酸内切酶对pCAGGS-HA-~(K141N)HSP22和pCAGGS-HA-~(wt)HSP22进行酶切得到线性化目的片段,然后进行微纤维注射。pCAGGS-HA-~(K141N)HSP22线性化片段进行三次微纤维注射,共注射640枚受精卵,生下24只仔鼠,经PCR和测序分析,获得4只携带人类HSP22基因K141N突变的转基因首建鼠,编号为Tg642、Tg677、Tg679和Tg681。首建鼠Tg642已到交配年龄,使其与正常小鼠进行交配,已生下3批共23只F1代小鼠,经PCR鉴定,获得4只携带人类HSP22基因K141N突变的F1代转基因小鼠,编号为Be423、Be435、Bf84和Bf86,经Western Blot分析,该Tg642系小鼠并不表达目的蛋白,其他三个品系小鼠有待进一步鉴定。pCAGGS-HA-~(wt)HSP22线性化片段进行一次微纤维注射,共注射210枚受精卵,生下19只仔鼠,经PCR和测序分析,获得4只携带人类HSP22基因的转基因首建鼠,编号为Tg646、Tg648、Tg649和Tg661。
在获得更多pCAGGS-HA-~(K141N)HSP22子代转基因阳性小鼠的基础上,我们将继续进行外源性突变HSP22蛋白的表达分析,如成功表达,再进行下一步的行为学、电生理学和病理学等方面的分析,以期获得CMT2L的转基因小鼠模型,为CMT的分子发病机制和治疗研究奠定基础。在获得pCAGGS-HA-~(wt)HSP22子代转基因阳性小鼠的基础上,分析外源性HSP22蛋白的过表达情况,如能得到过表达HSP22蛋白的转基因阳性小鼠,后续的工作可围绕HSP22的神经保护作用进行,例如用HSP22过表达的转基因阳性小鼠与阿尔茨海默病(Alzhermer's Disease,AD)、帕金森病(Parkinson's Disease,PD)、肌萎缩侧索硬化症(Amyotrophic LateralSclerosis,ALS)等神经退行性疾病的小鼠模型进行交配,也使这些神经退行性疾病的小鼠模型过表达HSP22蛋白,观察HSP22对上述神经退行性疾病的病理改变是否有保护作用,从而为神经退行性疾病的治疗研究提供新的思路。
Charcot-Marie-Tooth disease(CMT),also known as hereditary motor and sensory neuropathy(HMSN),is the most common hereditary peripheral neuropathy with highly clinical and genetic heterogeneity. CMT is characterized by progressive and symmetric distal muscle atrophy,weakness,hyporeflexia and hypoesthesia in distal limbs.The incidence of CMT is about 1/2500.According to the electrophysiological and histopathological criteria,CMT can be divided into two forms:the demyelinating form(CMT1)and the axonal form(CMT2).Several modes of inheritance have been described in CMT,including autosomal dominant(AD),autosomal recessive(AR)and X-linked dominant or recessive(XD/XR).With the advancement of the biogenetics,so far 32 gene loci have been identified and 22 distinct genes have been cloned.In 2004,we found a large Chinese CMT2 family in Hunan and Hubei provinces which was proved to be a novel genotype designated as CMT2L.After mapping the locus to a 6.8cM region at chromosome 12q24.2-12q24.3,we identified a novel 423G→T mutation of HSP22 gene and confirmed amino-acid Change K141N as the causative gene defect in CMT2L.
Although many mutations of a number of genes have been associated with CMT,the disease mechanisms caused by each gene may be different.The main mechanisms include dosage effect,loss of function, gain of function or dominant-negative effect.Many researches have found that HSP22 not only can interact with HSP27,but may be involved in the modulation of HSP27 activities.The K141N mutation in the HSP22 protein does not disrupt interaction with HSP27,but strengthen it, leading to the formation of aggregates.So,the K141N mutation may have a gain-of-function and cause CMT.To confirm the presumption,we can construct the transgenic mice which carry the K141N mutation of human HSP22 gene through microinjection.
Recently studies showed that HSP27 gene mutations could also be associated with CMT.The phenotypes caused by HSP22 or HSP27 are similar.This would be a good clue not only for the researches about the normal function of sHSPs,but the researches about the pathogenesis of CMT.By over expression of heat shock protein 27(HSP27)in transgenic mice,many scholars have found that HSP27 not only could reduce cell death in the hippocampus associated with seizures and reduce infarct size in cardiac or brain ischemia but has significant cytoprotective properties in rescuing nerve injury,maintaining muscle function.Whether HSP22 has the similar properties as HSP27,there are still no relevant reports and no transgenic mice over expression HSP22.It is necessary to establish the transgenic mice model over expressing HSP22 for improving our understanding the normal function of HSP22 and learn more about the pathogenesis of HSP22 mutations.
To construct the transgenic mouse models carrying the mutation K141N of human HSP22 gene or the wild-type human HSP22 gene,we constructed pCAGGS-HA-~(K141N)HSP22 and pCAGGS-HA-~(wt)HSP22 transgenic expression vectors,pCAGGS-HA-~(K141N)HSP22 and pCAGGS-HA-~(wt)HSP22 could express effectively in eukaryocytes such as COS7 and HEK293T cells through confocal microscopy and western blot analysis.We also confirmed that mutant HSP22 protein formed large aggregates predominantly located around the nucleus and wild HSP22 protein distributed diffusively in the cytosol and nucleus.A prospective 25.5kDa protein band of HA-tagged HSP22 could be specificity detected by Western blot with a monoclonal antibody to the HA tag.Our results showed that pCAGGS-HA-~(K141N)HSP22 and pCAGGS-HA-~(wt)HSP22 could be used to further transgenic researches.The linearized DNA was cut out of the pCAGGS-HA-~(K141N)HSP22 or pCAGGS-HA-~(wt)HSP22 vectors by SalI,HindⅢand BsaⅪI digestion,purified and used to generate the transgenic mice.The linearized pCAGGS-HA-~(K141N)HSP22 was microinjected into 640 fertilized eggs from C57BL mice,which were subsequently transferred to pseudopregnant recipients.24 babies were produced.Among them,4 transgenic founder mice(Tg642,Tg677, Tg679,Tg681)carrying the mutation K141N of human HSP22 gene were identified by PCR and direct sequence.Tg642 can breed very well and have produced 23 F1 offsping.Among them,4 transgenic F1 mice (Be423,Be435,Bf84,Bf86)carrying the mutation K141N of human HSP22 gene were identified by PCR.But the Tg642 line mice didn't express the human HSP22 protein and can not be used for further researches.The linearized pCAGGS-HA-~(wt)HSP22 was microinjected into 210 fertilized eggs from C57BL mice.19 babies were produced.Among them,4 transgenic founder mice(Tg646,Tg648,Tg649,Tg661)carrying human HSP22 gene were identified by PCR and direct sequence.
We will analyze the expression of exogenous mutant HSP22 protein if we can get more offspring carrying the mutation K141N of human HSP22 gene.If our transgenic mice express the human mutant HSP22 protein,we will observe whether they have the similar behavior, electrophysiology or pathology features as human CMT2L disease.This will establish foundations for the pathogenesis and therapy researches of CMT.Similarly,if the transgenic founder mice carrying the human HSP22 gene could breed well,we will analyze whether these mice could over express human HSP22 protein.We could analyze the neuron protective function of HSP22 in the transgenic mice over expression of HSP22 protein.Many sHSPs are often upregulated and accumulate into inclusion bodies in many neurodegenerative diseases.This suggests that sHSPs may be potent suppressors of neurodegeneration.Some transgenic mice of neurodegenerative disease such as Alzhermer's disease(AD), Parkinson's disease(PD)or Amyotrophic Lateral Sclerosis(ALS)have been generated.We could make those transgenic mice also to over express HSP22 by mating them with our HSP22 over expressed transgenic mice.Then we can observe whether HSP22 have an effect on the pathological changes on the transgenic mice of neurodegenerative disease.This will provide a new idea about the therapy for those neurodegenerative diseases.
研究表明,CMT各亚型致病基因的分子发病机制并不完全一样,可能通过致病基因的剂量效应、功能丧失、功能获得或显性-负性作用而致病。国外研究表明,HSP22与HSP27存在蛋白-蛋白相互作用,而且还发现,HSP22可能与调节HSP27的活性有关,HSP22基因的K141N突变后并没有破坏其编码蛋白与HSP27的相互作用,相反,这种相互作用还增强了并且导致蛋白聚集物的形成,表明K141N突变可能是通过功能获得作用而致病。为了证实上述推测,我们拟应用微纤维注射技术构建HSP22基因K141N的转基因小鼠模型,使小鼠携带人类突变的HSP22蛋白,验证该突变的功能获得作用。
最近的研究发现,HSP27突变后也可引起CMT,HSP22和HSP27基因突变可以引起同样的疾病表型,这无疑为CMT发病机制的相关性研究提供了一个很好的线索和思路。通过对HSP27过表达转基因小鼠模型进行研究,发现HSP27不仅对癫痫后的病理改变、心肌缺血和脑缺血之后的再灌注损伤都有保护作用,而且对神经损伤修复、肌肉功能的维持也有重要作用。HSP22是否具有同样的功能,目前国内外尚无系列的研究报道,也无关于HSP22的过表达转基因小鼠构建的报道。因此,为了更好的研究HSP22基因的功能及该基因突变后的分子致病机制,构建HSP22的过表达转基因小鼠模型是非常必要的。
为了构建携带人类HSP22基因K141N突变和野生型HSP22基因的转基因小鼠模型,我们成功构建了pCAGGS-HA-~(K141N)HSP22和pCAGGS-HA-~(wt)HSP22两个转基因表达载体。通过激光共聚焦显微镜和Western Blot分析,证实了pCAGGS-HA-~(K141N)HSP22和pCAGGS-HA-~(wt)HSP22可在真核细胞有效表达,并验证了K141N突变型HSP22在活体外细胞系中形成以核周分布为主的聚合物,野生型HSP22在活体外细胞系中弥散分布于胞浆和胞核内。应用HA单克隆抗体,可以特异性检测出约25.5kDa大小的带HA-tag的HSP22蛋白。体外实验证实pCAGGS-HA-~(K141N)HSP22和pCAGGS-HA-~(wt)HSP22能用于转基因小鼠的构建后,我们用SalⅠ、HindⅢ和BsaⅪ三个核酸内切酶对pCAGGS-HA-~(K141N)HSP22和pCAGGS-HA-~(wt)HSP22进行酶切得到线性化目的片段,然后进行微纤维注射。pCAGGS-HA-~(K141N)HSP22线性化片段进行三次微纤维注射,共注射640枚受精卵,生下24只仔鼠,经PCR和测序分析,获得4只携带人类HSP22基因K141N突变的转基因首建鼠,编号为Tg642、Tg677、Tg679和Tg681。首建鼠Tg642已到交配年龄,使其与正常小鼠进行交配,已生下3批共23只F1代小鼠,经PCR鉴定,获得4只携带人类HSP22基因K141N突变的F1代转基因小鼠,编号为Be423、Be435、Bf84和Bf86,经Western Blot分析,该Tg642系小鼠并不表达目的蛋白,其他三个品系小鼠有待进一步鉴定。pCAGGS-HA-~(wt)HSP22线性化片段进行一次微纤维注射,共注射210枚受精卵,生下19只仔鼠,经PCR和测序分析,获得4只携带人类HSP22基因的转基因首建鼠,编号为Tg646、Tg648、Tg649和Tg661。
在获得更多pCAGGS-HA-~(K141N)HSP22子代转基因阳性小鼠的基础上,我们将继续进行外源性突变HSP22蛋白的表达分析,如成功表达,再进行下一步的行为学、电生理学和病理学等方面的分析,以期获得CMT2L的转基因小鼠模型,为CMT的分子发病机制和治疗研究奠定基础。在获得pCAGGS-HA-~(wt)HSP22子代转基因阳性小鼠的基础上,分析外源性HSP22蛋白的过表达情况,如能得到过表达HSP22蛋白的转基因阳性小鼠,后续的工作可围绕HSP22的神经保护作用进行,例如用HSP22过表达的转基因阳性小鼠与阿尔茨海默病(Alzhermer's Disease,AD)、帕金森病(Parkinson's Disease,PD)、肌萎缩侧索硬化症(Amyotrophic LateralSclerosis,ALS)等神经退行性疾病的小鼠模型进行交配,也使这些神经退行性疾病的小鼠模型过表达HSP22蛋白,观察HSP22对上述神经退行性疾病的病理改变是否有保护作用,从而为神经退行性疾病的治疗研究提供新的思路。
Charcot-Marie-Tooth disease(CMT),also known as hereditary motor and sensory neuropathy(HMSN),is the most common hereditary peripheral neuropathy with highly clinical and genetic heterogeneity. CMT is characterized by progressive and symmetric distal muscle atrophy,weakness,hyporeflexia and hypoesthesia in distal limbs.The incidence of CMT is about 1/2500.According to the electrophysiological and histopathological criteria,CMT can be divided into two forms:the demyelinating form(CMT1)and the axonal form(CMT2).Several modes of inheritance have been described in CMT,including autosomal dominant(AD),autosomal recessive(AR)and X-linked dominant or recessive(XD/XR).With the advancement of the biogenetics,so far 32 gene loci have been identified and 22 distinct genes have been cloned.In 2004,we found a large Chinese CMT2 family in Hunan and Hubei provinces which was proved to be a novel genotype designated as CMT2L.After mapping the locus to a 6.8cM region at chromosome 12q24.2-12q24.3,we identified a novel 423G→T mutation of HSP22 gene and confirmed amino-acid Change K141N as the causative gene defect in CMT2L.
Although many mutations of a number of genes have been associated with CMT,the disease mechanisms caused by each gene may be different.The main mechanisms include dosage effect,loss of function, gain of function or dominant-negative effect.Many researches have found that HSP22 not only can interact with HSP27,but may be involved in the modulation of HSP27 activities.The K141N mutation in the HSP22 protein does not disrupt interaction with HSP27,but strengthen it, leading to the formation of aggregates.So,the K141N mutation may have a gain-of-function and cause CMT.To confirm the presumption,we can construct the transgenic mice which carry the K141N mutation of human HSP22 gene through microinjection.
Recently studies showed that HSP27 gene mutations could also be associated with CMT.The phenotypes caused by HSP22 or HSP27 are similar.This would be a good clue not only for the researches about the normal function of sHSPs,but the researches about the pathogenesis of CMT.By over expression of heat shock protein 27(HSP27)in transgenic mice,many scholars have found that HSP27 not only could reduce cell death in the hippocampus associated with seizures and reduce infarct size in cardiac or brain ischemia but has significant cytoprotective properties in rescuing nerve injury,maintaining muscle function.Whether HSP22 has the similar properties as HSP27,there are still no relevant reports and no transgenic mice over expression HSP22.It is necessary to establish the transgenic mice model over expressing HSP22 for improving our understanding the normal function of HSP22 and learn more about the pathogenesis of HSP22 mutations.
To construct the transgenic mouse models carrying the mutation K141N of human HSP22 gene or the wild-type human HSP22 gene,we constructed pCAGGS-HA-~(K141N)HSP22 and pCAGGS-HA-~(wt)HSP22 transgenic expression vectors,pCAGGS-HA-~(K141N)HSP22 and pCAGGS-HA-~(wt)HSP22 could express effectively in eukaryocytes such as COS7 and HEK293T cells through confocal microscopy and western blot analysis.We also confirmed that mutant HSP22 protein formed large aggregates predominantly located around the nucleus and wild HSP22 protein distributed diffusively in the cytosol and nucleus.A prospective 25.5kDa protein band of HA-tagged HSP22 could be specificity detected by Western blot with a monoclonal antibody to the HA tag.Our results showed that pCAGGS-HA-~(K141N)HSP22 and pCAGGS-HA-~(wt)HSP22 could be used to further transgenic researches.The linearized DNA was cut out of the pCAGGS-HA-~(K141N)HSP22 or pCAGGS-HA-~(wt)HSP22 vectors by SalI,HindⅢand BsaⅪI digestion,purified and used to generate the transgenic mice.The linearized pCAGGS-HA-~(K141N)HSP22 was microinjected into 640 fertilized eggs from C57BL mice,which were subsequently transferred to pseudopregnant recipients.24 babies were produced.Among them,4 transgenic founder mice(Tg642,Tg677, Tg679,Tg681)carrying the mutation K141N of human HSP22 gene were identified by PCR and direct sequence.Tg642 can breed very well and have produced 23 F1 offsping.Among them,4 transgenic F1 mice (Be423,Be435,Bf84,Bf86)carrying the mutation K141N of human HSP22 gene were identified by PCR.But the Tg642 line mice didn't express the human HSP22 protein and can not be used for further researches.The linearized pCAGGS-HA-~(wt)HSP22 was microinjected into 210 fertilized eggs from C57BL mice.19 babies were produced.Among them,4 transgenic founder mice(Tg646,Tg648,Tg649,Tg661)carrying human HSP22 gene were identified by PCR and direct sequence.
We will analyze the expression of exogenous mutant HSP22 protein if we can get more offspring carrying the mutation K141N of human HSP22 gene.If our transgenic mice express the human mutant HSP22 protein,we will observe whether they have the similar behavior, electrophysiology or pathology features as human CMT2L disease.This will establish foundations for the pathogenesis and therapy researches of CMT.Similarly,if the transgenic founder mice carrying the human HSP22 gene could breed well,we will analyze whether these mice could over express human HSP22 protein.We could analyze the neuron protective function of HSP22 in the transgenic mice over expression of HSP22 protein.Many sHSPs are often upregulated and accumulate into inclusion bodies in many neurodegenerative diseases.This suggests that sHSPs may be potent suppressors of neurodegeneration.Some transgenic mice of neurodegenerative disease such as Alzhermer's disease(AD), Parkinson's disease(PD)or Amyotrophic Lateral Sclerosis(ALS)have been generated.We could make those transgenic mice also to over express HSP22 by mating them with our HSP22 over expressed transgenic mice.Then we can observe whether HSP22 have an effect on the pathological changes on the transgenic mice of neurodegenerative disease.This will provide a new idea about the therapy for those neurodegenerative diseases.
引文
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