探討在斑馬魚小腦發育中ttbk2對神經先驅細胞的影響;Investigation of the effect of ttbk2 on neuronal progenitors during cerebellar development in zebrafish

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Title:	探討在斑馬魚小腦發育中ttbk2對神經先驅細胞的影響;Investigation of the effect of ttbk2 on neuronal progenitors during cerebellar development in zebrafish
Authors:	林佩誼;Lin, Pei-Yi
Contributors:	生命科學系
Keywords:	ttbk2;小腦發育;神經先驅細胞;ttbk2;cerebellar development;Purkinje cell progenitors;Granule cell progenitors
Date:	2021-09-03
Issue Date:	2021-12-07 11:28:06 (UTC+8)
Publisher:	國立中央大學
Abstract:	初級纖毛在神經系統發育中扮演重要的角色，若初級纖毛發生缺陷，容易引發神經系統發育上的問題。初級纖毛缺陷容易導致的小腦發育問題，包含Purkinje cells減少、granule cells減少、granule cells progenitors減少。　　TTBK2 (tau tubulin kinase 2)對初級纖毛的生成有重要的作用，若TTBK2發生問題，也容易產生神經系統發育疾病。在臨床上，脊髓小腦萎縮症被認為和TTBK2的缺陷有關，TTBK2的缺陷造成病患小腦萎縮、Purkinje cells和granule cells的減少。因此，TTBK2在小腦發育中扮演著重要的角色。　　為了研究TTBK2對小腦發育的影響，王又婷利用CRISPR-Cas9編輯斑馬魚的基因，產生ttbk2有缺陷的斑馬魚，ttbk2缺陷的斑馬魚也有小腦發育上的問題，包含Purkinje cells和granule cells軸突的減少。　　在本篇研究中，我們首先歸納出ttbk2a和ttbk2b在斑馬魚腦中的表現位置，在成魚的腦中，ttbk2a和ttbk2b在腦的腔室附近皆有較高的表現量；在小腦中，ttbk2a主要表現在granule cells，而ttbk2b主要表現在Purkinje cells。在胚胎階段，ttbk2b在一顆細胞階段的受精卵就開始表現。而ttbk2a在受精卵發育後24小時才開始。在幼魚中，ttbk2a和ttbk2b都表現在整個頭中。　　第二，我們發現初級纖毛在成魚小腦中主要表現在molecular layer。　　第三，我們歸納出ttbk2對granule cells progenitors的增生有重要的影響，對Purkinje cells的分化也有重要的影響。　　最後，我們也確認Purkinje cells和granule cells軸突的減少是因為初級纖毛的缺陷造成。 ;Primary cilia are required for the developmental signaling pathway. Primary cilia are important for cerebellar development. Ciliary defects result in cerebellar ataxia with decreased Purkinje cells, granule cells and granule cells progenitors. TTBK2 is located at basal body and it is important for ciliogenesis. Spinocerebellar ataxia type 11 (SCA11) is a neurodegeneration disease, and it is related with mutations on TTBK2. SCA11 is characterized with decreased Purkinje cells and decreased granule cells. It suggests that TTBK2 is important for cerebellar development. To investigate the role of TTBK2 during cerebellar development, Yu-ting Wang used CRISPR-Cas9 to generate ttbk2 mutants with protein truncation at kinase domain of ttbk2. Cilia were almost lost and Purkinje cells and axon terminals of granule cells were largely decreased in ttbk2 mutant. In this study, first, the distribution of ttbk2a and ttbk2b in zebrafish cerebellum were characterized. ttbk2a was expressed in granule cells, while ttbk2b was expressed in Purkinje cells. ttbk2b was expressed in 1-cell stage embryo, while ttbk2a was not expressed until 24 hpf in the head of embryos. Second, the location of primary cilia in cerebellum in adult zebrafish was identified. Primary cilia were located in the molecular layer of cerebellum in adult. Third, the role of ttbk2 during cerebellar development was also characterized. ttbk2 was important for the proliferation of granule cells progenitors. ttbk2 was important for differentiation of Purkinje cells. Finally, it was confirmed that decreased Purkinje cells and axon terminals of granule cells were caused by ciliary deficit.
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