title: SNX27 Deletion Causes Hydrocephalus by Impairing Ependymal Cell Differentiation and Ciliogenesis.
abstract: Hydrocephalus is a brain disorder derived from CSF accumulation due to defects in CSF clearance. Although dysfunctional apical cilia in the ependymal cell layer are causal to the onset of hydrocephalus, mechanisms underlying proper ependymal cell differentiation are largely unclear. SNX27 is a trafficking component required for normal brain function and was shown previously to suppress γ-secretase-dependent amyloid precursor protein and Notch cleavage. However, it was unclear how SNX27-dependent γ-secretase inhibition could contribute to brain development and pathophysiology. Here, we describe and characterize an Snx27-deleted mouse model for the ependymal layer defects of deciliation and hydrocephalus. SNX27 deficiency results in reductions in ependymal cells and cilia density, as well as severe postnatal hydrocephalus. Inhibition of Notch intracellular domain signaling with γ-secretase inhibitors reversed ependymal cells/cilia loss and dilation of lateral ventricles in Snx27-deficient mice, giving strong indication that Snx27 deletion triggers defects in ependymal layer formation and ciliogenesis through Notch hyperactivation. Together, these results suggest that SNX27 is essential for ependymal cell differentiation and ciliogenesis, and its deletion can promote hydrocephalus pathogenesis.
  
  
  
  Down's syndrome (DS) in humans and mouse models has been shown previously to confer a high risk for the development of pathological hydrocephalus. Because we have previously described SNX27 as a component that is consistently downregulated in DS, we present here a robust Snx27-deleted mouse model that produces hydrocephalus and associated ciliary defects with complete penetrance. In addition, we find that γ-secretase/Notch modulation may be a candidate drug target in SNX27-associated hydrocephalus such as that observed in DS. Based on these findings, we anticipate that future study will determine whether modulation of a SNX27/Notch/γ-secretase pathway can also be of therapeutic interest to congenital hydrocephalus.
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Medical College and the Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen 361102, China, wangx@xmu.edu.cn xuh@sbpdiscovery.org.|Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Medical College and the Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen 361102, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Medical College and the Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen 361102, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: I-Chu
authors.identifier: 0000-0001-8522-6524
authors.initials: IC
authors.lastname: Tseng
authors.affiliation: Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Timothy
authors.initials: T
authors.lastname: Huang
authors.affiliation: Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Yingjun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Medical College and the Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen 361102, China.
authors.forename: Qiuyang
authors.identifier: 0000-0001-7843-3365
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Medical College and the Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen 361102, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Medical College and the Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen 361102, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Luo
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Medical College and the Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen 361102, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Medical College and the Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen 361102, China.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Institute for Biomedical Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361005, China, and.|Institute of Molecular and Cell Biology, Singapore 138673, Singapore.
authors.forename: Wanjin
authors.identifier: 0000-0002-1719-8960
authors.initials: W
authors.lastname: Hong
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Medical College and the Collaborative Innovation Center for Brain Science, Xiamen University, Xiamen 361102, China, wangx@xmu.edu.cn xuh@sbpdiscovery.org.|Neuroscience Initiative, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California 92037.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
mesh_terms: D022005:Adherens Junctions / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002923:Cilia / Q000473:pathology / Q000502:physiology*; D004805:Ependyma / Q000166:cytology / Q000473:pathology*; D005347:Fibroblasts / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006849:Hydrocephalus / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061251:Primary Cell Culture; D051880:Receptors, Notch / Q000378:metabolism; D058305:Sorting Nexins / Q000235:genetics / Q000502:physiology*
chemical_list: D051880:Receptors, Notch; C500393:Snx27 protein, mouse; D058305:Sorting Nexins; D053829:Amyloid Precursor Protein Secretases; D005978:Glutathione
keywords: SNX27; cilia; ependymal cell; hydrocephalus; trafficking; γ-secretase