Assembly of primary cilia and its role in proliferative skin disorders = 일차 섬모의 형성 기전 및 과증식성 피부질환에서의 역할 연구

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Present in almost all mammalian cells, primary cilia are conserved cellular organelles that mediate several signaling pathways, including hedgehog, Wnt, and Notch pathways. The biogenesis of primary cilia is dynamically regulated by cell cycle, signaling pathways and mechanical stress. By regulating hedgehog activity, primary cilia modulate the development of hedgehog pathway-dependent cancers, including basal cell carcinoma and medulloblas-toma. Therefore, delineating the exact mechanisms of ciliogenesis for each cell type and the role of primary cilia in human disease has emerged as an important issue. Accordingly, the present study was undertaken to investigate the role of human microspherule protein 1 (MCRS1) in ciliogenesis and to evaluate the role of primary cilia and the hedgehog pathway in hyperproliferative skin disorders. Previous studies have shown MCRS1 to be important to several cellular activities, includ-ing transcriptional regulation, mitotic spindle assembly, mTOR signaling, and tumorigenesis. Although MCRS1 has been reported to bind to the dynein regulator NDE1, a functional interaction between MCRS1 and cytoplasmic dynein has yet to be addressed. In the present study, MCRS1 was found to be essential to dynein-dependent cargo transport to the cen-trosome and to play a role in primary cilium formation. In addition to the nucleus, where most MCRS1 protein was located, MCRS1 was also discovered in centriolar satellites, as well as the centrosome, in a microtubule- and dynein-dependent manner. Knockdown of MCRS1 resulted in a dispersion of centriolar satellites, whose establishment depends on cytoplasmic dynein. In contrast, NDE1 was not necessary for proper distribution of centrio-lar satellites, indicating a functional distinction between MCRS1 and NDE1. Moreover, binding between DYNC1I1 and NDE1 was weakened in the presence of MCRS1, as it also binds to DYNC1I1. Unlike NDE1, which acts as a negative regulator of ciliogenesis, MCRS1 played a positive role in the initiation of ciliogenesis, possibly through its interac-tion with TTBK2. To elucidate the in vivo functions of MCRS1, we established a zebrafish line carrying a mcrs1 mutation using TALEN technology. Homozygous mcrs1 mutants ex-hibited reductions in the sizes of the brain and the eyes due to excessive apoptosis. Addi-tionally, mcrs1 mutants failed to develop distinct layers in the retina, and showed a defect in melatonin-induced aggregation of melanosomes in melanophores. These phenotypes were reminiscent of zebrafish dynein mutants. Reduced ciliogenesis was also apparent in the ol-factory placodes of mcrs1 mutants. Collectively, the findings of the present study identified MCRS1 as a dynein-interacting protein critical for centriolar satellite formation and cilio-genesis. In chapter 2, the role of primary cilia and the hedgehog pathway in hyperproliferative skin disorders, including psoriasis, was evaluated. Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferation of keratinocytes. Although the activation of Th17- and Th22-mediated immunities has been considered as a major cause of psoriasis, the precise mechanism of uncontrolled keratinocyte proliferation remains unclear. Upon analysis of GSE datasets, hedgehog target genes, including Gli1 and PTCH1, were found to be down-regulated in the lesional skin of psoriasis patients. Thus, Gli1-positive keratinocytes, which show active hedgehog pathway signaling, were examined in psoriasis lesions. In imiquimod-induced psoriasis-like skin, Gli1-positive cells proliferated from the hair bulge area to the interfollicular epidermis. This expansion in Gli1-positive cells was strongly sup-pressed upon treatment with hedgehog activator. In contrast, treatment with vismodegib, an inhibitor of the hedgehog pathway, aggravated the development of psoriasis. Accordingly, since primary cilia are crucial to activation of the hedgehog pathway, the presence of prima-ry cilia on the lesional skin of psoriasis patients was evaluated. Both the lesional skin from psoriasis patients and imiquimod-induced psoriasis-like lesions showed increases in ciliated keratinocytes, compared to normal skin. Next, the role of primary cilia in the development of psoriasis was investigated in keratinocyte-specific conditional knockout of ciliogenic genes in mice. In $K14Cre; IFT20^{F/F}$ mice, the presence of ciliated keratinocytes was rarely noted, even in imiquimod-treated lesions. In these mice, ear thicknesses were greater than those in $K14Cre; IFT20^{F/WT}$ mice in response to imiquimod treatment. These findings sug-gested that the hedgehog pathway and primary cilia play a role in psoriasis development. In conclusion, the results of the present study not only improve our understating of cili-ogenesis, but also provide new insights into the pathogenesis of psoriasis. Further investiga-tion into the involvement of the hedgehog pathway and primary cilia in psoriasis develop-ment might help establish novel treatments for psoriasis.
Kim, Joonresearcher김준researcher
한국과학기술원 :의과학대학원,
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학위논문(박사) - 한국과학기술원 : 의과학대학원, 2016.2,[vii, 92 p. :]


primary cilia▼aMCRS1▼adynein hedgehog pathway▼apsoriasis; 일차 섬모▼aMCRS1▼a다이네인▼a헤지혹 신호전달▼a건선

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