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Study on the signal transduction pathway involved in CNTF-mediated neuronal differentiation

Title
Study on the signal transduction pathway involved in CNTF-mediated neuronal differentiation
Authors
엄의영
Issue Date
2000
Department/Major
대학원 생물과학과
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
최원자, 안상미
Abstract
인간과 고등척추동물에 있어서 손상 받은 중추신경계는 재생되지 않고 퇴행하여 영구적으로 기능을 상실하게 된다. 중치신경계의 신경재생을 촉진시킬 수 있는 신경성 장인자들을 찾는 연구 중에서 CNTF와 LIF가 특이적으로 순수 배양된 망막신경절세포의 axonal outgrowth를 촉진시킴이 보고되었다(Jo et al., 1999). CNTF와 LIF 외에 망막신경절세포의 axonal outgrowth를 촉진시킬 수 있는 다른 cytokine을 찾기 위하여 CNTF, LIF, CT-1,IL-6를 선택하여 처리하였으나, CNTF와 LIF가 가장 효과적으로 망막신경절세포의 axonal outgrowth를 촉진시켰다. 또한 CNTF와 LIF는 neuroblastoma 세포주인 SH-SY5Y cell의 분화를 촉진시켰다. CNTF가 매개하는 axonal outgrowth에 관련된 세포신호전달체계를 조사하기 위해 CNTF receptor(CNTFRα, LIFβ and gp130), Jak family(Jak1, Jak2, Tyk2 and Jak3) 그리고 STATs (STAT1, STAT3)의 발현여부를 면역조직염색 방법을 통하여 조사하였다. 조사된 CNTF와 LIF는 망막신경절세포와 SH-SY5y cells에서 STAT3을 활성화 시켰다. 활성화 된 STAT3는 핵으로 이동하였으며, c-fos 같은 유전자의 전사를 촉진시켰다. 망막신경절세포에서 CNTF 또는 LIF는 MAPK의 활성화를 시키지 못했으나, SH-SY5Y cell의 경우 CNTF 또는 LIF는 Jak-STAT pathway 뿐만 아니라 p44/p42 MAPK의 활성화에도 영향을 미쳤다. CNTF는 SH-SY5Y cell의 분화를 촉진시키고 GAP-43 단백질의 양도 증가시켰으나 이에 따른 GAP-43의 mRNA양에는 변화가 없었다. 그러나 분화하는 동안에 bcl-2의 mRNA가 증가하였으며 이는 bcl-2가 분화에 관련된다는 것을 간접적으로 증명해 준다. 위의 연구결과는 CNTF 또는 LIF는 axonal outgrowth와 differentiation을 촉진해 주며, 이 때에 SATA3가 관련되고, GAP-43와 bcl-2가 분화에 관련됨을 증명한다.;In human and higher vertebrates, injured CNS neurons fail to regenerate. In efforts to identify the neurotrophic factors which are able to stimulate axonal outgrowth of CNS neuron, it was reported that ciliary neurotrophic factor(CNTF) and leukemia inhibitory factor(LIF) profoundly stimulated axonal out rat retinal ganglion cells (RGCs) purified by immunopanning (Jo et al., 1999). In order to explore the significance of each gp130 and LIFR subunit in neuritogenic activity mediated by CNTF-related cytokines, CNTF, LIF, CT-1 and IL-6 were selected and the effects of cytokines on axonal outgrowth were examined. CNTF and LIF had most efficiency stimulating axonal outgrowth in GGCs. CNTF and LIF also promoted differentiation of SH-SY5Y cells. To understand signaling pathways involved in CNTF-mediated axonal outgrowth, expression patterns of CNTF receptors(CNTFR, LIFR and gp130), Jak family (Jak1, Jak2, Tyk2 and Jak3) and STATs (STAT1,3) were examined. Immunoreactivities of all three receptors, Jak family and STATs were detected in RGCs. CNTF or LIF activated STAT3 both in RGCs and in SH-SY5Y cells. Activated STAT3 translocated to the nucleus and activated down stream gene such as c-fos. In RGCs CNTF and LIF did not activate p44/p42 MAP kinase. In SH-SY5Y cells CNTF and LIF activate both STAT3 and p44/p42 MAPK. Although CNTF stimulated defferentition, GAP-43 mRNA levels did not altered. IN contrast bcl-2 mRNA level was increased after CNTF treatment. These data indicate that CNTF and LIF has effects on axonal outgrowth and differentiation and that STAT3 pathway is involved in CNTF or LIF-mediated axonal outgrowth and neuronal differentiation.
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