Ulk4 Is Essential for Ciliogenesis and CSF Flow

Liu, Min; Guan, Zhenlong; Shen, Qin; Lalor, Pierce; FitzGerald, Una; O’Brien, Timothy; Dockery, Peter; Shen, Sanbing

doi:10.1523/jneurosci.0621-16.2016

Cited by 40 publications

(75 citation statements)

References 50 publications

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“…These patients manifested heterogeneous clinical symptoms, including developmental delay, behavioral problems, severe learning difficulties, severe language delay, speech delay, and others ( Table 1 ). Recently, it has been reported that ULK4 regulates the FOXJ1 pathway and an array of other molecules involved in ciliogenesis [Liu et al, 2016b].…”

Section: Discussionmentioning

confidence: 99%

Intragenic Microdeletion of ULK4 and Partial Microduplication of BRWD3 in Siblings with Neuropsychiatric Features and Obesity

Tassano¹,

Uccella²,

Giacomini³

et al. 2018

Cytogenet Genome Res

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ULK4 and BRWD3 deletions have been identified in patients with developmental/language delay and intellectual disability. Both genes play pivotal roles in brain development. In particular, ULK4 encodes serine/threonine kinases that are critical for the development and function of the nervous system, while BRWD3 plays a crucial role in ubiquitination, as part of the ubiquitin/proteasome system. We report on 2 brothers, aged 7.6 and 20 years, presenting with cognitive impairment, epilepsy, autistic features, hearing loss, and obesity. Array-CGH analysis demonstrated 2 rare CNVs in both siblings: a paternally inherited microdeletion of ∼145 kb at 3p22.1, disrupting the ULK4 gene, and a maternally inherited microduplication of ∼117 kb at Xq21.1 including only the BRWD3 gene. As already described for other recurrent syndromes with variable phenotype, these findings are challenging in genetic counseling because of an evident variable penetrance. We discuss the possible correlations between the clinical phenotype of our patients and the function of the genes involved in these microrearrangements.

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Section: Discussionmentioning

confidence: 99%

Intragenic Microdeletion of ULK4 and Partial Microduplication of BRWD3 in Siblings with Neuropsychiatric Features and Obesity

Tassano¹,

Uccella²,

Giacomini³

et al. 2018

Cytogenet Genome Res

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show abstract

“…They belong to ULK families already implicated in flagellum-related functions in animals (35,36) with the mammalian ULK Fused demonstrated to be essential for construction of motile cilia (35). Plant orthologs of both kinases were shown to be critical for the phragmoplast organization, resembling the function of plant kinesin-15s (37,38).…”

Section: The Fc Is a Membrane Junction Attached By Two Types Of Kinesmentioning

confidence: 99%

Protein diversity in discrete structures at the distal tip of the trypanosome flagellum

Varga

Moreira-Leite

Portman

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The distal end of the eukaryotic flagellum/cilium is important for axonemal growth and signaling and has distinct biomechanical properties. Specific flagellum tip structures exist, yet their composition, dynamics, and functions are largely unknown. We used biochemical approaches to identify seven constituents of the flagella connector at the tip of an assembling trypanosome flagellum and three constituents of the axonemal capping structure at the tips of both assembling and mature flagella. Both tip structures contain evolutionarily conserved as well as kinetoplastid-specific proteins, and component assembly into the structures occurs very early during flagellum extension. Localization and functional studies reveal that the flagella connector membrane junction is attached to the tips of extending microtubules of the assembling flagellum by a kinesin-15 family member. On the opposite side, a kinetoplastid-specific kinesin facilitates attachment of the junction to the microtubules in the mature flagellum. Functional studies also suggest roles of several other components and the definition of subdomains in the tip structures.

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“…Two proteins that are homologous to geminin-Mcidas and GemC1-promote the expression of the Foxj1 and c-Myb transcription factors, all of which are necessary for ependymal cell differentiation (Malaterre et al 2008;Jacquet et al 2009;Stubbs et al 2012;Tan et al 2013;Kyrousi et al 2015). The transcription factors Trp73 (Yang et al 2000;GonzalezCano et al 2016), Yap (Park et al 2016), and Gli3 (Wang et al 2014) and the kinase Ulk4 (Liu and Guan 2016) are also required for ependymal cell differentiation. There are also many genes that, when mutated, impair cilia function and can contribute to the development of hydrocephalus (Fliegauf et al 2007;Tissir et al 2010;Ohata et al 2014).…”

mentioning

confidence: 99%

Prdm16 is required for the maintenance of neural stem cells in the postnatal forebrain and their differentiation into ependymal cells

et al. 2017

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We and others showed previously that PR domain-containing 16 (Prdm16) is a transcriptional regulator required for stem cell function in multiple fetal and neonatal tissues, including the nervous system. However, Prdm16 germline knockout mice died neonatally, preventing us from testing whether Prdm16 is also required for adult stem cell function. Here we demonstrate that Prdm16 is required for neural stem cell maintenance and neurogenesis in the adult lateral ventricle subventricular zone and dentate gyrus. We also discovered that Prdm16 is required for the formation of ciliated ependymal cells in the lateral ventricle. Conditional Prdm16 deletion during fetal development using Nestin-Cre prevented the formation of ependymal cells, disrupting cerebrospinal fluid flow and causing hydrocephalus. Postnatal Prdm16 deletion using Nestin-CreER T2 did not cause hydrocephalus or prevent the formation of ciliated ependymal cells but caused defects in their differentiation. Prdm16 was required in neural stem/ progenitor cells for the expression of Foxj1, a transcription factor that promotes ependymal cell differentiation. These studies show that Prdm16 is required for adult neural stem cell maintenance and neurogenesis as well as the formation of ependymal cells.

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Ulk4 Is Essential for Ciliogenesis and CSF Flow

Cited by 40 publications

References 50 publications

Intragenic Microdeletion of <b><i>ULK4</i></b> and Partial Microduplication of <b><i>BRWD3</i></b> in Siblings with Neuropsychiatric Features and Obesity

Intragenic Microdeletion of <b><i>ULK4</i></b> and Partial Microduplication of <b><i>BRWD3</i></b> in Siblings with Neuropsychiatric Features and Obesity

Protein diversity in discrete structures at the distal tip of the trypanosome flagellum

Prdm16 is required for the maintenance of neural stem cells in the postnatal forebrain and their differentiation into ependymal cells

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