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 remain...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-11-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471631467X |
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doaj-3a5ecf5bb9b64b5cab80d85b37eba2ff |
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| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants Cell Reports dendrite growth dendritic spine autism spectrum disorder actin cytoskeleton neurodevelopment genetic variants MARK1 excitatory synapse Wnt signaling |
| author_facet |
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 |
| author_sort |
Vickie Kwan |
| title |
DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants |
| title_short |
DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants |
| title_full |
DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants |
| title_fullStr |
DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants |
| title_full_unstemmed |
DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants |
| title_sort |
dixdc1 phosphorylation and control of dendritic morphology are impaired by rare genetic variants |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2016-11-01 |
| description |
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. |
| topic |
dendrite growth dendritic spine autism spectrum disorder actin cytoskeleton neurodevelopment genetic variants MARK1 excitatory synapse Wnt signaling |
| url |
http://www.sciencedirect.com/science/article/pii/S221112471631467X |
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doaj-3a5ecf5bb9b64b5cab80d85b37eba2ff2020-11-25T00:43:12ZengElsevierCell Reports2211-12472016-11-011771892190410.1016/j.celrep.2016.10.047DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic VariantsVickie Kwan0Durga Praveen Meka1Sean H. White2Claudia L. Hung3Nicholas T. Holzapfel4Susan Walker5Nadeem Murtaza6Brianna K. Unda7Birgit Schwanke8Ryan K.C. Yuen9Kendra Habing10Chloe Milsom11Kristin J. Hope12Ray Truant13Stephen W. Scherer14Froylan Calderon de Anda15Karun K. Singh16Stem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, CanadaCenter for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, GermanyStem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, CanadaDepartment of Biochemistry and Biomedical Sciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, CanadaStem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, CanadaThe 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, CanadaStem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, CanadaStem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, CanadaCenter for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, GermanyThe 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, CanadaStem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, CanadaStem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, CanadaStem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, CanadaDepartment of Biochemistry and Biomedical Sciences, Michael G. DeGroote School of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, CanadaThe 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, CanadaCenter for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, GermanyStem Cell and Cancer Research Institute, Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, CanadaThe 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.http://www.sciencedirect.com/science/article/pii/S221112471631467Xdendrite growthdendritic spineautism spectrum disorderactincytoskeletonneurodevelopmentgenetic variantsMARK1excitatory synapseWnt signaling |