A CLN6-CRMP2-KLC4 complex regulates anterograde ER-derived vesicle trafficking in cortical neurites

Koh, Seung yon; Cain, Jacob T.; Magee, Helen; White, Katherine A.; Rechtzigel, Mitch; Meyerink, Brandon; Leppert, Hannah; Timm, Derek; Morgan, Jeremy P; Johnson, Tyler B.; Grove, Bryon; Khanna, Rajesh; Hensley, Kenneth; Brudvig, Jon; Weimer, Jill M.

doi:10.1101/2021.09.16.460653

Cited by 3 publications

(2 citation statements)

References 51 publications

(75 reference statements)

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“…The increase in MT velocity could suggest an increase in MT sliding or altered regulation or localization of polymerization-promoting MAPs such as CRMP2 ( Nakamura et al, 2020 ). CRMP2 has been reported to influence MT polymerization and stabilization and has been found in complex with KLC4, supporting its potential role in KLC4-mediated effects on MTs ( Liz et al, 2014 ; Koh et al, 2021 ). The model of KLC4 as a mediator of microtubule dynamics is also supported by the similarities in phenotype between klc4 mutants and kinesore treatment.…”

Section: Discussionmentioning

confidence: 79%

KLC4 shapes axon arbors during development and mediates adult behavior

Haynes

Burnett

et al. 2022

eLife

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Development of elaborate and polarized neuronal morphology requires precisely regulated transport of cellular cargos by motor proteins such as kinesin-1. Kinesin-1 has numerous cellular cargos which must be delivered to unique neuronal compartments. The process by which this motor selectively transports and delivers cargo to regulate neuronal morphogenesis is poorly understood, although the cargo-binding kinesin light chain (KLC) subunits contribute to specificity. Our work implicates one such subunit, KLC4, as an essential regulator of axon branching and arborization pattern of sensory neurons during development. Using live imaging approaches in klc4 mutant zebrafish, we show that KLC4 is required for stabilization of nascent axon branches, proper microtubule (MT) dynamics, and endosomal transport. Furthermore, KLC4 is required for proper tiling of peripheral axon arbors: in klc4 mutants, peripheral axons showed abnormal fasciculation, a behavior characteristic of central axons. This result suggests that KLC4 patterns axonal compartments and helps establish molecular differences between central and peripheral axons. Finally, we find that klc4 mutant larva are hypersensitive to touch and adults show anxiety-like behavior in a novel tank test, implicating klc4 as a new gene involved in stress response circuits.

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Section: Discussionmentioning

confidence: 79%

KLC4 shapes axon arbors during development and mediates adult behavior

Haynes

Burnett

et al. 2022

eLife

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“…The increase in MT velocity could suggest an increase in MT sliding or altered regulation or localization of polymerization-promoting MAPs such as CRMP2 (Nakamura, Ohshima, and Goshima 2020). CRMP2 has been reported to influence MT polymerization and stabilization and has been found in complex with KLC4, supporting its potential role in KLC4-mediated effects on MTs (Liz et al 2014;Koh et al 2021).…”

Section: Discussionmentioning

confidence: 94%

KLC4 shapes axon arbors during development and mediates adult behavior

Haynes

He²,

Jean-Pierre

et al. 2021

Preprint

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Development of elaborate and polarized neuronal morphology requires precisely regulated transport of cellular cargos by motor proteins such as kinesin-1. Kinesin-1 has numerous cellular cargos which must be delivered to unique neuronal compartments. The process by which this motor selectively transports and delivers cargo to regulate neuronal morphogenesis is poorly understood. Our work implicates one kinesin light chain subunit, KLC4, as an essential regulator of axon branching and arborization pattern of sensory neurons during development. Using several live imaging approaches in klc4 mutant zebrafish, we show that KLC4 is required for stabilization of nascent axon branches and for proper microtubule (MT) dynamics. Furthermore, KLC4 is required for the contact repulsion necessary for tiling of peripheral axon arbors: in klc4 mutants, peripheral axons showed abnormal fasciculation, a behavior characteristic of central axons, suggesting that KLC4 patterns axonal compartments and helps define axon identity. Finally, we find that klc4 mutant adults show anxiety-like behavior in a novel tank test, implicating klc4 as a novel gene involved in stress response circuits.

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Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center

Rus

Weissensteiner

Pereira

et al. 2022

Orphanet J Rare Dis

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Background Ceroid lipofuscinoses neuronal 6 (CLN6) disease belongs to the neuronal ceroid lipofuscinoses (NCLs), complex and genetically heterogeneous disorders with wide geographical and phenotypic variation. The first clinical signs usually appear between 18 months and 8 years, but examples of later-onset have also been reported. Common manifestations include ataxia, seizures, vision impairment, and developmental regression. Because these are shared by other neurological diseases, identification of CLN6 genetic variants is imperative for early diagnosis. Results We present one of the largest cohorts to date of genetically diagnosed CLN6 patients screened at a single center. In total 97 subjects, originating from 20 countries were screened between 2010 and 2020. They comprised 86 late-infantile, eight juvenile, and three adult-onset cases (two patients with Kufs disease type A, and one with teenage progressive myoclonic epilepsy). The male to female ratio was 1.06: 1.00. The age at referral was between six months and 33 years. The time from disease onset to referral ranged from less than 1 month to 8.3 years. The clinical phenotype consisted of a combination of symptoms, as reported before. We characterized a total of 45 distinct variants defining 45 distinct genotypes. Twenty-four were novel variants, some with distinct geographic associations. Remarkably, c.257A > G (p.H86R) was present in five out of 23 unrelated Egyptian individuals but in no patients from other countries. The most common genotype was homozygosity for the c.794_796del in-frame deletion. It was present in about one-third of CLN6 patients (28 unrelated cases, and 2 familial cases), all with late-infantile onset. Variants with a high likelihood of causing loss of CLN6 function were found in 21% of cases and made up 33% of all distinct variants. Forty-four percent of variants were classified as pathogenic or likely pathogenic. Conclusions Our study significantly expands the number of published clinical cases and the mutational spectrum of disease-associated CLN6 variants, especially for the Middle Eastern and North African regions. We confirm previous observations regarding the most prevalent symptoms and recommend including CLN6 in the genetic diagnosis of patients presenting with early-onset abnormalities of the nervous system, musculoskeletal system, and eye.

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A CLN6-CRMP2-KLC4 complex regulates anterograde ER-derived vesicle trafficking in cortical neurites

Cited by 3 publications

References 51 publications

KLC4 shapes axon arbors during development and mediates adult behavior

KLC4 shapes axon arbors during development and mediates adult behavior

KLC4 shapes axon arbors during development and mediates adult behavior

Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center

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