title: Ulk4 Is Essential for Ciliogenesis and CSF Flow.
abstract: Ciliopathies are an emerging class of devastating disorders with pleiotropic symptoms affecting both the central and peripheral systems and commonly associated with hydrocephalus. Even though ciliary components and three master transcriptional regulators have been identified, little is known about the signaling molecules involved. We previously identified a novel gene, Unc51-like-kinase 4 (ULK4), as a risk factor of neurodevelopmental disorders. Here we took multidisciplinary approaches and uncovered essential roles of Ulk4 in ciliogenesis. We show that Ulk4 is predominantly expressed in the ventricular system, and Ulk4(tm1a/tm1a) ependymal cells display reduced/disorganized cilia with abnormal axonemes. Ulk4(tm1a/tm1a) mice exhibit dysfunctional subcommissural organs, obstructive aqueducts, and impaired CSF flow. Mechanistically, we performed whole-genome RNA sequencing and discovered that Ulk4 regulates the Foxj1 pathway specifically and an array of other ciliogenesis molecules. This is the first evidence demonstrating that ULK4 plays a vital role in ciliogenesis and that deficiency of ULK4 can cause hydrocephalus and ciliopathy-related disorders.
  
  
  
  Ciliopathies are an emerging class of devastating disorders with pleiotropic symptoms affecting both the central and peripheral systems. Ciliopathies are commonly associated with hydrocephalus, and Unc51-like-kinase 4 (Ulk4) has been identified as one of 12 genes causing hydrocephalus in mutants. Here we uncover an essential role of Ulk4 in ciliogenesis. Ulk4 is predominantly expressed in the ventricles, and mutant ependymal cells display reduced/disorganized/nonfunctional motile cilia with abnormal axonemes and impaired CSF flow. Ulk4 modulates expression of the master regulator of ciliogenesis, Foxj1, and other ciliogenesis molecules. This is the first report demonstrating a vital role of Ulk4 in ciliogenesis. ULK4 deficiency may be implicated in human hydrocephalus and other ciliopathy-related disorders.
authors.affiliation: Regenerative Medicine Institute, School of Medicine, National University of Ireland Galway, Galway, Ireland.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Physiology, College of Life Science, Hebei Normal University, Shijiazhuang 050024, China, sanbing.shen@nuigalway.ie zlguan60@mail.hebtu.edu.cn.
authors.forename: Zhenlong
authors.identifier: 0000-0003-1930-6029
authors.initials: Z
authors.lastname: Guan
authors.affiliation: Center for Stem Cell Biology and Regenerative Medicine, Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Anatomy Department, School of Medicine, National University of Ireland, Galway, Ireland, and.
authors.forename: Pierce
authors.initials: P
authors.lastname: Lalor
authors.affiliation: National Centre for Biomedical Engineering Science, Galway Neuroscience Centre, National University of Ireland, Galway, Ireland.
authors.forename: Una
authors.identifier: 0000-0002-8019-6546
authors.initials: U
authors.lastname: Fitzgerald
authors.affiliation: Regenerative Medicine Institute, School of Medicine, National University of Ireland Galway, Galway, Ireland.
authors.forename: Timothy
authors.identifier: 0000-0001-9028-5481
authors.initials: T
authors.lastname: O'Brien
authors.affiliation: Anatomy Department, School of Medicine, National University of Ireland, Galway, Ireland, and.
authors.forename: Peter
authors.initials: P
authors.lastname: Dockery
authors.affiliation: Regenerative Medicine Institute, School of Medicine, National University of Ireland Galway, Galway, Ireland, sanbing.shen@nuigalway.ie zlguan60@mail.hebtu.edu.cn.
authors.forename: Sanbing
authors.initials: S
authors.lastname: Shen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001931:Brain Mapping; D002552:Cerebral Ventricles / Q000378:metabolism / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000235:genetics* / Q000502:physiology; D002923:Cilia / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000072661:Ciliopathies / Q000134:cerebrospinal fluid* / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006849:Hydrocephalus / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C481963:FOXJ1 protein, mouse; C500666:FOXJ1 protein, rat; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C570299:Ulk4 protein, human
keywords: CSF; Ulk4; ciliogenesis; hydrocephalus; hypomorph mouse; neurodevelopmental disorder