Perturbed Wnt signaling leads to neuronal migration delay, altered interhemispheric connections and impaired social behavior

Nature Communications
Riccardo BocchiJozsef Z Kiss

Abstract

Perturbed neuronal migration and circuit development have been implicated in the pathogenesis of neurodevelopmental diseases; however, the direct steps linking these developmental errors to behavior alterations remain unknown. Here we demonstrate that Wnt/C-Kit signaling is a key regulator of glia-guided radial migration in rat somatosensory cortex. Transient downregulation of Wnt signaling in migrating, callosal projection neurons results in delayed positioning in layer 2/3. Delayed neurons display reduced neuronal activity with impaired afferent connectivity causing permanent deficit in callosal projections. Animals with these defects exhibit altered somatosensory function with reduced social interactions and repetitive movements. Restoring normal migration by overexpressing the Wnt-downstream effector C-Kit or selective chemogenetic activation of callosal projection neurons during a critical postnatal period prevents abnormal interhemispheric connections as well as behavioral alterations. Our findings identify a link between defective canonical Wnt signaling, delayed neuronal migration, deficient interhemispheric connectivity and abnormal social behavior analogous to autistic characteristics in humans.

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Citations

Feb 9, 2020·International Journal of Molecular Sciences·Carolyn Klocke, Pamela J Lein
Jun 14, 2020·Nature Communications·Xiaoyun SunYuhua Sun
Jun 20, 2019·Frontiers in Cellular Neuroscience·Janne HakanenFadel Tissir
Sep 23, 2020·Toxics·Harmanpreet Kaur PanesarPamela J Lein
Oct 13, 2020·Frontiers in Cell and Developmental Biology·Rocío Valle-BautistaAnayansi Molina-Hernández
Jan 18, 2021·Current Opinion in Neurobiology·Artur Kania
Jul 9, 2021·Frontiers in Cell and Developmental Biology·Ling HuBing Lang

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Datasets Mentioned

BETA
AB3080

Methods Mentioned

BETA
FACS
PCA
transfection
Assay
flow cytometry
PCR

Software Mentioned

GraphPad Prism
Genego
HTSeq Python library
Neuralynx
ANYmaze
Pictureframe
Bioconductor edgeR package
Matlab
TopHat
MetaMorph

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