Mutant α2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome

Nugent, Alicia A.; Park, Jong G.; Wei, Yan; Tenney, Alan P.; Gilette, Nicole M.; DeLisle, Michelle M.; Chan, Wai‐Man; Cheng, Long; Engle, Elizabeth C.

doi:10.1172/jci88502

Cited by 29 publications

(34 citation statements)

References 45 publications

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“…Although it is likely that the axon guidance mechanisms in the abducens nerve are different from those of other ocular nerves, the exact molecular mechanisms remain to be elucidated. Recently, Nugent et al reported that knock-in mice with an α2-chimerin gain-of-function missense mutation, identified in CCDD patients, showed a similar stalled phenotype in the abducens nerves, with variable penetrance [ 25 ]. More importantly, they also demonstrated that axons in α2-chimerin-knockout mice, a loss-of-function model, and mice with knockout of the upstream adhesion molecule, EphA4, exhibited the wandering phenotype in abducens nerves as also detected in our DINE mutant mice.…”

Section: Discussionmentioning

confidence: 99%

Distinct functional consequences of ECEL1/DINE missense mutations in the pathogenesis of congenital contracture disorders

Nagata

Takahashi

Kiryu‐Seo

et al. 2017

acta neuropathol commun

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Endothelin-converting enzyme-like 1 (ECEL1, also termed DINE in rodents), a membrane-bound metalloprotease, has been identified as a gene responsible for distal arthrogryposis (DA). ECEL1-mutated DA is generally characterized by ocular phenotypes in addition to the congenital limb contractures that are common to all DA subtypes. Until now, the consequences of the identified pathogenic mutations have remained incompletely understood because of a lack of detailed phenotypic analyses in relevant mouse models. In this study, we generated a new knock-in mouse strain that carries an ECEL1/DINE pathogenic G607S missense mutation, based on a previous study reporting atypical DA hindlimb phenotypes in two siblings with the mutation. We compared the morphological phenotypes of G607S knock-in mice with C760R knock-in mice that we previously established. Both C760R and G607S knock-in mouse embryos showed similar axonal arborization defects with normal trajectory patterns from the spinal cord to the target hindlimb muscles, as well as axon guidance defects of the abducens nerves. Intriguingly, distinct phenotypes in DINE protein localization and mRNA expression were identified in these knock-in mouse lines. For G607S, DINE mRNA and protein expression was decreased or almost absent in motor neurons. In the C760R mutant mice DINE was expressed and localized in the somata of motor neurons but not in axons. Our mutant mouse data suggest that ECEL1/DINE G607S and C760R mutations both lead to motor innervation defects as primary causes in ECEL1-mutated congenital contracture disorders. However, the functional consequences of the two mutations are distinct, with loss of axonal transport of ECEL1/DINE in C760R mutants and mRNA expression deficits in G607S mutants.Electronic supplementary materialThe online version of this article (10.1186/s40478-017-0486-9) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Distinct functional consequences of ECEL1/DINE missense mutations in the pathogenesis of congenital contracture disorders

Nagata

Takahashi

Kiryu‐Seo

et al. 2017

acta neuropathol commun

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“…The specification of the abducens motor neurons relies on Hox-dependent positional values (Gaufo et al, 2003;Manzanares et al, 1997;Prince et al, 1998). Following specification, axons of abducens motor neurons are guided by extrinsic directional cues, including semaphorin and ephrin, through activation of downstream signaling pathways that modulate cytoskeletal dynamics (Ferrario et al, 2012;Nugent et al, 2017). Consistent with these molecular mechanisms, the causative genetic loci for Duane retraction syndrome (DRS), a congenital type of strabismus, encode transcription factors for hindbrain patterning (HOXA1 and MAFB) (Park et al, 2016;Tischfield et al, 2005) and a Rac-GAP modulating cytoskeletal dynamics (CHN1/a2chimaerin) (Miyake et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Protocadherin-Mediated Cell Repulsion Controls the Central Topography and Efferent Projections of the Abducens Nucleus

Asakawa

Kawakami

2018

Cell Reports

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Cranial motor nuclei in the brainstem innervate diverse types of head and neck muscles. Failure in establishing these neuromuscular connections causes congenital cranial dysinnervation disorders (CCDDs) characterized by abnormal craniofacial movements. However, mechanisms that link cranial motor nuclei to target muscles are poorly understood at the molecular level. Here, we report that protocadherin-mediated repulsion mediates neuromuscular connection in the ocular motor system in zebrafish. We identify pools of abducens motor neurons that are topographically arranged according to soma size and convergently innervate a single muscle. Disruptions of Duane retraction syndrome-associated transcription factors reveal that these neurons require Mafba/MAFB, but not Sall4/SALL4, for differentiation. Furthermore, genetic perturbations of Pcdh17/protocadherin-17 result in defective axon growth and soma clumping, thereby abolishing neuromuscular connectivity. Our results suggest that protocadherin-mediated repulsion forms the central topography and efferent projection pattern of the abducens nucleus following Mafba-dependent specification and imply potential involvement of protocadherins in CCDD etiology.

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“…Following specification, axons of abducens motor neurons are guided by extrinsic directional cues, including semaphorin and ephrin, through activation of downstream signaling pathways that modulate cytoskeletal dynamics (Ferrario et al, 2012) (Nugent et al, 2017). Consistent with these molecular mechanisms, the causative genetic loci for Duane retraction syndrome (DRS), a congenital type of strabismus, encode transcription factors for hindbrain patterning (HOXA1 and MAFB) (Tischfield et al, 2005) (Park et al, 2016) and a Rac-GAP modulating cytoskeletal dynamics (CHN1/α2-chimaerin) (Miyake et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Protocadherin-mediated cell repulsion controls the central topography and efferent projections of the abducens nucleus

Asakawa

Kawakami

2018

Preprint

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SummaryCranial motor nuclei in the brainstem innervate diverse types of head and neck muscles.Failure in establishing these neuromuscular connections causes congenital cranial dysinnervation disorders (CCDDs) characterized by abnormal craniofacial movements.However, mechanisms that link cranial motor nuclei to target muscles are poorly understood at the molecular level. Here, we report that protocadherin-mediated repulsion mediates neuromuscular connection in the ocular motor system in zebrafish.We identify pools of abducens motor neurons that are topographically arranged according to soma size and convergently innervate a single muscle. Disruptions of Duane retraction syndrome-associated transcription factors reveal that these neurons require Mafba/MAFB, but not Sall4/SALL4, for differentiation. Furthermore, genetic perturbations of Pcdh17/Protocadherin-17 result in defective axon growth and soma clumping, thereby abolishing neuromuscular connectivity. Our results suggest that protocadherin-mediated repulsion forms the central topography and efferent projection pattern of the abducens nucleus following Mafba-dependent specification, and imply potential involvement of protocadherins in CCDD etiology.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Mutant α2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome

Cited by 29 publications

References 45 publications

Distinct functional consequences of ECEL1/DINE missense mutations in the pathogenesis of congenital contracture disorders

Distinct functional consequences of ECEL1/DINE missense mutations in the pathogenesis of congenital contracture disorders

Protocadherin-Mediated Cell Repulsion Controls the Central Topography and Efferent Projections of the Abducens Nucleus

Protocadherin-mediated cell repulsion controls the central topography and efferent projections of the abducens nucleus

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