한빛사 논문
Hyowon Hong, PhD1,6, Kwangsic Joo, MD/PhD2,6, Sang Min Park, MS1, Jimyung Seo, MD3, Min Hwan Kim, MD/PhD3, EunBie Shin, MS1, Hae Il Cheong, MD4,5, Jeong Ho Lee, MD/PhD1,3, and Joon Kim, PhD1,3,7
1 Biomedical Science and Engineering Interdisciplinary Program, KAIST, Daejeon, Korea
2 Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
3 Graduate School of Medical Science and Engineering, KAIST, Daejeon, Korea
4 Department Pediatrics, Seoul National University Children’s Hospital, Seoul, Korea
5 Research Coordination Center for Rare Disease, Seoul National University Hospital, Seoul, Korea
6 These authors contributed equally to the work
7 Corresponding author
Abstract
Objective
JBTS17 is a major gene mutated in ciliopathies such as Joubert syndrome and oral‐facial‐digital syndrome type VI. Most patients with loss of function mutations in JBTS17 exhibit cerebellar vermis hypoplasia and brain stem malformation. However, some patients with JBTS17 mutations show microcephaly and abnormal gyration. We examined potential roles of JBTS17 in neurogenesis to understand the pathological mechanism of JBTS17‐related cortical abnormalities.
Methods
We examined subcellular localization and cell cycle‐dependent expression of JBTS17 proteins using anti‐JBTS17 antibodies and JBTS17 expression vectors. We also performed knockdown experiments to determined roles of JBTS17 in human cells, and demonstrated mitotic functions of JBTS17 using immunostaining and live imaging. We examined the involvement of JBTS17 in cortical neurogenesis using mouse in utero electroporation technique.
Results
We found that JBTS17 localizes to the kinetochore and the level of JBTS17 is regulated by cell cycle‐dependent proteolysis. Depletion of JBTS17 disrupts chromosome alignment and spindle pole orientation, resulting in mitotic delay. JBTS17 interacts with LIS1 and influences LIS1 localization. Depletion of Jbts17 in the developing mouse cortex interferes with the mitotic progression of neural progenitors and the migration of postmitotic neurons.
Interpretation
LIS1 is implicated in lissencephaly, but altered dosage of LIS1 has been also associated with microcephaly syndromes. Our results suggest that JBTS17 contributes to mitotic progression by interacting with LIS1, and abnormal mitosis is an underlying mechanism of the microcephaly phenotype in JBTS17‐related ciliopathies. We propose that understanding extraciliary roles of ciliopathy proteins is important to elucidate pathological mechanisms underlying diverse ciliopathy phenotypes.
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