Planar cell polarity genes Frizzled3a, Vangl2, and Scribble are required for spinal commissural axon guidance

Sun, Simón D.; Purdy, Ashley M.; Walsh, Gregory S.

doi:10.1186/s12868-016-0318-z

Cited by 16 publications

(8 citation statements)

References 66 publications

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“…Such phenotype is associated with failure of the callosal axons to cross the midline rather than an outgrowth problem towards the midline. Although we cannot completely exclude an autonomous role of Scrib in axon guidance as shown during axonal misrouting at the chiasm 39 and during spinal commissures formation in zebrafish 40 , Scrib expression in the midline glia and the disorganization of that structure in Emx1-Scrib −/− mutant mice suggest that a non-autonomous Scrib -dependent mechanism affects the crossing of the axons of the CC. Mutations in guidance cues expressed by the midline glia typically lead to a Probst bundles phenotype; thus, we can envision that Scrib deletion affects midline glial cells maturation and/or guidance cues secretion 41 as seen in other systems 42 , 43 .…”

Section: Discussionmentioning

confidence: 85%

Early loss of Scribble affects cortical development, interhemispheric connectivity and psychomotor activity

Ezan

Moreau

Mamo

et al. 2021

Sci Rep

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Neurodevelopmental disorders arise from combined defects in processes including cell proliferation, differentiation, migration and commissure formation. The evolutionarily conserved tumor-suppressor protein Scribble (Scrib) serves as a nexus to transduce signals for the establishment of apicobasal and planar cell polarity during these processes. Human SCRIB gene mutations are associated with neural tube defects and this gene is located in the minimal critical region deleted in the rare Verheij syndrome. In this study, we generated brain-specific conditional cKO mouse mutants and assessed the impact of the Scrib deletion on brain morphogenesis and behavior. We showed that embryonic deletion of Scrib in the telencephalon leads to cortical thickness reduction (microcephaly) and partial corpus callosum and hippocampal commissure agenesis. We correlated these phenotypes with a disruption in various developmental mechanisms of corticogenesis including neurogenesis, neuronal migration and axonal connectivity. Finally, we show that Scrib cKO mice have psychomotor deficits such as locomotor activity impairment and memory alterations. Altogether, our results show that Scrib is essential for early brain development due to its role in several developmental cellular mechanisms that could underlie some of the deficits observed in complex neurodevelopmental pathologies.

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Section: Discussionmentioning

confidence: 85%

Early loss of Scribble affects cortical development, interhemispheric connectivity and psychomotor activity

Ezan

Moreau

Mamo

et al. 2021

Sci Rep

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“…Wnts were first found to be axon guidance molecules directing the growth of axons along the anterior-posterior (rostral-caudal) axis of the rodent spinal cord in development 37 , 38 and direct dorsal-ventral topographic mapping in the chick visual system 39 ( Figure 1(a) ). Subsequent work showed that the function of Wnts in guiding axons along the A-P axis is conserved in a number of animal species, including rodents, chick, zebrafish, and Caenorhabditis elegans , 40 – 45 as well as the function in topographic mapping in Drosophila visual system. 46 Wnts attract axons via a non-canonical pathway, planar cell polarity pathway 40 , 47 – 51 but repel axons which express Ryk as a Wnt coreceptor.…”

Section: Targeting Axon Guidance To Promote Functional Recoverymentioning

confidence: 99%

Targeting axon guidance cues for neural circuit repair after spinal cord injury

Zou

2020

J Cereb Blood Flow Metab

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At least two-thirds of spinal cord injury cases are anatomically incomplete, without complete spinal cord transection, although the initial injuries cause complete loss of sensory and motor functions. The malleability of neural circuits and networks allows varied extend of functional restoration in some individuals after successful rehabilitative training. However, in most cases, the efficiency and extent are both limited and uncertain, largely due to the many obstacles of repair. The restoration of function after anatomically incomplete injury is in part made possible by the growth of new axons or new axon branches through the spared spinal cord tissue and the new synaptic connections they make, either along the areas they grow through or in the areas they terminate. This review will discuss new progress on the understanding of the role of axon guidance molecules, particularly the Wnt family proteins, in spinal cord injury and how the knowledge and tools of axon guidance can be applied to increase the potential of recovery. These strategies, combined with others, such as neuroprotection and rehabilitation, may bring new promises. The recovery strategies for anatomically incomplete spinal cord injuries are relevant and may be applicable to traumatic brain injury and stroke.

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“…Such phenotype is associated with failure of the callosal axons to cross the midline rather than an outgrowth problem towards the midline. Although we cannot completely exclude an autonomous role of Scrib in axon guidance as shown during axonal misrouting at the chiasm 37 and during spinal commissures formation in zebrafish 38 , Scrib expression in the midline glia and the disorganization of that structure in Emx1-Scrib -/mutant mice suggest that a non-autonomous Scrib-dependent mechanism affects the crossing of the axons of the CC. Mutations in guidance cues expressed by the midline glia typically lead to a Probst bundles phenotype; thus, we can envision that Scrib deletion affects midline glial cells maturation and/or guidance cues secretion 39 as seen in other systems 40,41 .…”

Section: Discussionmentioning

confidence: 85%

Early loss of Scribble affects cortical development and interhemispheric connectivity resulting in psychomotor dysregulation

Ezan¹,

Moreau²,

Mamo³

et al. 2019

Preprint

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226/300 words) 29 Neurodevelopmental disorders often arise from combined defects in processes 30 including cell proliferation, differentiation, neuronal migration, axonal pathfinding and 31 commissure formation. Cell polarity proteins serve as a nexus to transduce signals for 32 the establishment of these essential processes. Scribble (Scrib) is an evolutionarily 33 conserved polarity protein that is known to regulate the establishment of apicobasal and 34 planar cell polarity. Mutations in the human SCRIB gene are associated with neural tube 35 defects and this gene is located in the minimal critical region deleted in the rare 36 Verheij/8q24.3 deletion syndrome. In the present study, we evaluated the contribution of 37 Scrib to some of the neurological features found in patients with this syndrome, 38 including microcephaly and corpus callosum agenesis. Using various brain-specific 39 conditional mouse mutants and in utero electroporation experiments, we assessed the 40 impact of the spatio-temporal selective Scrib deletion on brain morphogenesis and 41 animal behavior. Our results showed that global embryonic deletion of Scrib in the 42 telencephalon lead to a reduction of cortical thickness and an alteration of 43 interhemispheric connectivity. In addition, we identified cell-autonomous effects of Scrib 44 on neuronal migration, and we suggest a non-cell-autonomous effect in axonal 45 guidance. Finally, comparative behavioral analysis showed that mice with Scrib 46 invalidation have psychomotor deficits. Altogether, our mouse models recapitulate a 47 number of the phenotypes associated with Verheij/8q24.3 deletion syndrome patients, 48 supporting the possibility that Scrib contributes to this rare disease. 49 50 callosum 53 3 55Author Summary (176/200 words) 56 The mammalian brain, seat of cognitive and behavioral processing, is the result of 57 numerous, complex but coordinated mechanisms of development such as cell 58 proliferation, migration, neuritogenesis, synaptogenesis and neural network formation. 59Patients with disruptions in these fundamental processes will typically exhibit 60 neurodevelopmental disorders. As such, the rare Verheij syndrome is a condition where 61 patients display some neurological features such as microcephaly (dramatic reduction in 62 brain cortical size) or agenesis of the corpus callosum (loss of the main commissure 63 between hemispheres). The human gene SCRIB is included within a region, identified 64 as 8q24.3, which is deleted in patients with this syndrome. In this paper, we generated 65 mouse models to assess the consequences of selective genetic inactivation of Scrib on 66 the brain architecture and function. From the neuroanatomical standpoint, we show that 67 Scrib controls the formation of the cerebral cortex and the corpus callosum. This is 68 correlated with behavioral deficits such as disrupted locomotion, learning and memory. 69Altogether, this work validates the association between Scrib loss and the brain-70 associated clinical features obs...

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Planar cell polarity genes Frizzled3a, Vangl2, and Scribble are required for spinal commissural axon guidance

Cited by 16 publications

References 66 publications

Early loss of Scribble affects cortical development, interhemispheric connectivity and psychomotor activity

Early loss of Scribble affects cortical development, interhemispheric connectivity and psychomotor activity

Targeting axon guidance cues for neural circuit repair after spinal cord injury

Early loss of Scribble affects cortical development and interhemispheric connectivity resulting in psychomotor dysregulation

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