DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants.
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.
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.
Vickie
V
Kwan
Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
Durga Praveen
DP
Meka
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.
Sean H
SH
White
Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Claudia L
CL
Hung
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.
Nicholas T
NT
Holzapfel
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.
Susan
S
Walker
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.
Nadeem
N
Murtaza
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.
Brianna K
BK
Unda
Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
Birgit
B
Schwanke
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.
Ryan K C
RKC
Yuen
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.
Kendra
K
Habing
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.
Chloe
C
Milsom
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.
Kristin J
KJ
Hope
Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada.
Ray
R
Truant
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.
Stephen W
SW
Scherer
Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
Froylan
F
Calderon de Anda
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.
Karun K
KK
Singh
D000818:Animals; D001321:Autistic Disorder / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008870:Microtubules / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013569:Synapses / Q000378:metabolism
C509983:Dixdc1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D020033:Protein Isoforms; C531338:MARK1 protein, mouse; D017346:Protein Serine-Threonine Kinases
MARK1; Wnt signaling; actin; autism spectrum disorder; cytoskeleton; dendrite growth; dendritic spine; excitatory synapse; genetic variants; neurodevelopment