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CSMD1 regulates bra...
CSMD1 regulates brain complement activity and circuit development
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- Baum, Matthew L (author)
- Harvard University
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- Wilton, Daniel K (author)
- Harvard University
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- Fox, Rachel G (author)
- Broad Institute
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- Carey, Alanna (author)
- Harvard University
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- Hsu, Yu-Han H (author)
- Broad Institute
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- Hu, Ruilong (author)
- Broad Institute
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- Jäntti, Henna J (author)
- Broad Institute
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- Fahey, Jaclyn B (author)
- Harvard University
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- Muthukumar, Allie K (author)
- Harvard University
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- Salla, Nikkita (author)
- Broad Institute
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- Crotty, William (author)
- Harvard University
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- Scott-Hewitt, Nicole (author)
- Harvard University
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- Bien, Elizabeth (author)
- Harvard University
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- Sabatini, David A (author)
- Harvard University
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- Lanser, Toby B (author)
- Harvard University
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- Frouin, Arnaud (author)
- Harvard University
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- Gergits, Frederick (author)
- Harvard University
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- Håvik, Bjarte (author)
- No affiliation available (private)
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- Gialeli, Chrysostomi (author)
- Lund University,Lunds universitet,Kardiovaskulär forskning - immunitet och ateroskleros,Forskargrupper vid Lunds universitet,Proteinkemi, Malmö,Kardiovaskulär forskning - translationella studier,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Cardiovascular Research - Immunity and Atherosclerosis,Lund University Research Groups,Protein Chemistry, Malmö,Cardiovascular Research - Translational Studies,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Nacu, Eugene (author)
- Broad Institute
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- Lage, Kasper (author)
- Broad Institute
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- Blom, Anna M (author)
- Lund University,Lunds universitet,Proteinkemi, Malmö,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Protein Chemistry, Malmö,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Eggan, Kevin (author)
- Harvard University
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- McCarroll, Steven A (author)
- Broad Institute
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- Johnson, Matthew B (author)
- Broad Institute
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- Stevens, Beth (author)
- Broad Institute
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(creator_code:org_t)
- English.
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In: Brain, Behavior, and Immunity. - 1090-2139.
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
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- Complement proteins facilitate synaptic elimination during neurodevelopmental pruning, but neural complement regulation is not well understood. CUB and Sushi Multiple Domains 1 (CSMD1) can regulate complement activity in vitro, is expressed in the brain, and is associated with increased schizophrenia risk. Beyond this, little is known about CSMD1 including whether it regulates complement activity in the brain or otherwise plays a role in neurodevelopment. We used biochemical, immunohistochemical, and proteomic techniques to examine the regional, cellular, and subcellular distribution as well as protein interactions of CSMD1 in the brain. To evaluate whether CSMD1 is involved in complement-mediated synapse elimination, we examined Csmd1-knockout mice and CSMD1-knockout human stem cell-derived neurons. We interrogated synapse and circuit development of the mouse visual thalamus, a process that involves complement pathway activity. We also quantified complement deposition on synapses in mouse visual thalamus and on cultured human neurons. Finally, we assessed uptake of synaptosomes by cultured microglia. We found that CSMD1 is present at synapses and interacts with complement proteins in the brain. Mice lacking Csmd1 displayed increased levels of complement component C3, an increased colocalization of C3 with presynaptic terminals, fewer retinogeniculate synapses, and aberrant segregation of eye-specific retinal inputs to the visual thalamus during the critical period of complement-dependent refinement of this circuit. Loss of CSMD1 in vivo enhanced synaptosome engulfment by microglia in vitro, and this effect was dependent on activity of the microglial complement receptor, CR3. Finally, human stem cell-derived neurons lacking CSMD1 were more vulnerable to complement deposition. These data suggest that CSMD1 can function as a regulator of complement-mediated synapse elimination in the CNS during development.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Baum, Matthew L
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Wilton, Daniel K
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Fox, Rachel G
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Carey, Alanna
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Hsu, Yu-Han H
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Hu, Ruilong
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show more...
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Jäntti, Henna J
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Fahey, Jaclyn B
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Muthukumar, Alli ...
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Salla, Nikkita
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Crotty, William
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Scott-Hewitt, Ni ...
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Bien, Elizabeth
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Sabatini, David ...
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Lanser, Toby B
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Frouin, Arnaud
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Gergits, Frederi ...
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Håvik, Bjarte
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Gialeli, Chrysos ...
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Nacu, Eugene
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Lage, Kasper
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Blom, Anna M
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Eggan, Kevin
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McCarroll, Steve ...
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Johnson, Matthew ...
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Stevens, Beth
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Brain, Behavior, ...
- By the university
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Lund University