DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants

Vickie Kwan; Durga Praveen Meka; Sean H White; Claudia L Hung; Nicholas T Holzapfel; Susan Walker; Nadeem Murtaza; Brianna K Unda; Birgit Schwanke; Ryan K C Yuen; Kendra Habing; Chloe Milsom; Kristin J Hope; Ray Truant; Stephen W Scherer; Froylan Calderon de Anda; Karun K Singh

doi:10.1016/j.celrep.2016.10.047

DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants

Cell Rep. 2016 Nov 8;17(7):1892-1904. doi: 10.1016/j.celrep.2016.10.047.

Authors

Vickie Kwan¹, Durga Praveen Meka², Sean H White¹, Claudia L Hung³, Nicholas T Holzapfel¹, Susan Walker⁴, Nadeem Murtaza¹, Brianna K Unda¹, Birgit Schwanke², Ryan K C Yuen⁴, Kendra Habing¹, Chloe Milsom¹, Kristin J Hope¹, Ray Truant³, Stephen W Scherer⁴, Froylan Calderon de Anda², Karun K Singh⁵

Affiliations

¹ Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
² Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
³ Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
⁴ The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, ON M5S 1A1, Canada.
⁵ Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada; Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address: singhk2@mcmaster.ca.

PMID: 27829159
DOI: 10.1016/j.celrep.2016.10.047

Abstract

The development of neural connectivity is essential for brain function, and disruption of this process is associated with autism spectrum disorders (ASDs). DIX domain containing 1 (DIXDC1) has previously been implicated in neurodevelopmental disorders, but its role in postnatal brain function remains unknown. Using a knockout mouse model, we determined that DIXDC1 is a regulator of excitatory neuron dendrite development and synapse function in the cortex. We discovered that MARK1, previously linked to ASDs, phosphorylates DIXDC1 to regulate dendrite and spine development through modulation of the cytoskeletal network in an isoform-specific manner. Finally, rare missense variants in DIXDC1 were identified in ASD patient cohorts via genetic sequencing. Interestingly, the variants inhibit DIXDC1 isoform 1 phosphorylation, causing impairment to dendrite and spine growth. These data reveal that DIXDC1 is a regulator of cortical dendrite and synaptic development and provide mechanistic insight into morphological defects associated with neurodevelopmental disorders.

Keywords: MARK1; Wnt signaling; actin; autism spectrum disorder; cytoskeleton; dendrite growth; dendritic spine; excitatory synapse; genetic variants; neurodevelopment.

MeSH terms

Animals
Autistic Disorder / metabolism
Autistic Disorder / pathology
Brain / metabolism
Dendrites / metabolism*
Dendritic Spines / metabolism
Intracellular Signaling Peptides and Proteins / deficiency
Intracellular Signaling Peptides and Proteins / metabolism*
Mice, Inbred C57BL
Mice, Knockout
Microtubules / metabolism
Mutation / genetics*
Mutation, Missense / genetics
Phosphorylation
Protein Isoforms / metabolism
Protein Serine-Threonine Kinases / metabolism
Synapses / metabolism

Substances

Dixdc1 protein, mouse
Intracellular Signaling Peptides and Proteins
Protein Isoforms
MARK1 protein, mouse
Protein Serine-Threonine Kinases

Grants and funding

CIHR/Canada