PUBLICATION
Mutations in the microtubule-associated protein MAP11 (C7orf43) cause microcephaly in humans and zebrafish
- Authors
- Perez, Y., Bar-Yaacov, R., Kadir, R., Wormser, O., Shelef, I., Birk, O.S., Flusser, H., Birnbaum, R.Y.
- ID
- ZDB-PUB-190205-7
- Date
- 2019
- Source
- Brain : a journal of neurology 142(3): 574-585 (Journal)
- Registered Authors
- Birnbaum, Ramon
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Cycle Proteins/metabolism
- Child
- Child, Preschool
- Cytokinesis
- Disease Models, Animal
- Female
- HeLa Cells
- Humans
- Male
- Microcephaly/etiology*
- Microcephaly/genetics*
- Microcephaly/metabolism
- Microtubule-Associated Proteins/genetics*
- Microtubule-Associated Proteins/metabolism
- Microtubules/genetics
- Mitosis
- Mutation
- Protein Serine-Threonine Kinases/metabolism
- Proto-Oncogene Proteins/metabolism
- Spindle Apparatus/genetics
- Tubulin/genetics
- Tubulin/metabolism
- Zebrafish/metabolism
- Zebrafish Proteins/metabolism
- PubMed
- 30715179 Full text @ Brain
Citation
Perez, Y., Bar-Yaacov, R., Kadir, R., Wormser, O., Shelef, I., Birk, O.S., Flusser, H., Birnbaum, R.Y. (2019) Mutations in the microtubule-associated protein MAP11 (C7orf43) cause microcephaly in humans and zebrafish. Brain : a journal of neurology. 142(3):574-585.
Abstract
Microtubule associated protein 11 (MAP11, previously termed C7orf43) encodes a highly conserved protein whose function is unknown. Through genome-wide linkage analysis combined with whole exome sequencing, we demonstrate that human autosomal recessive primary microcephaly is caused by a truncating mutation in MAP11. Moreover, homozygous MAP11-orthologue CRISPR/Cas9 knock-out zebrafish presented with microcephaly and decreased neuronal proliferation, recapitulating the human phenotype. We demonstrate that MAP11 is ubiquitously transcribed with high levels in brain and cerebellum. Immunofluorescence and co-immunoprecipitation studies in SH-SY5Y cells showed that MAP11 associates with mitotic spindles, co-localizing and physically associating with α-tubulin during mitosis. MAP11 expression precedes α-tubulin in gap formation of cell abscission at the midbody and is co-localized with PLK1, a key regulator of cytokinesis, at the edges of microtubule extensions of daughter cells post cytokinesis abscission, implicating a role in mitotic spindle dynamics and in regulation of cell abscission during cytokinesis. Finally, lentiviral-mediated silencing of MAP11 diminished SH-SY5Y cell viability, reducing proliferation rather than affecting apoptosis. Thus, MAP11 encodes a microtubule-associated protein that plays a role in spindle dynamics and cell division, in which mutations cause microcephaly in humans and zebrafish.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping