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
Affiliations
Vickie Kwan
Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
Durga Praveen Meka
Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany
Sean H. White
Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
Claudia L. Hung
Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
Nicholas T. Holzapfel
Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
Susan Walker
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
Nadeem Murtaza
Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
Brianna K. Unda
Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
Birgit Schwanke
Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany
Ryan K.C. Yuen
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
Kendra Habing
Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
Chloe Milsom
Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
Kristin J. Hope
Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
Ray Truant
Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
Stephen W. Scherer
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
Froylan Calderon de Anda
Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany
Karun K. Singh
Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
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.
