Spindle positioning in human cells relies on proper centriole formation and on the microcephaly proteins CPAP and STIL.
J Cell Sci
; 124(Pt 22): 3884-93, 2011 Nov 15.
Article
en En
| MEDLINE
| ID: mdl-22100914
Patients with MCPH (autosomal recessive primary microcephaly) exhibit impaired brain development, presumably due to the compromised function of neuronal progenitors. Seven MCPH loci have been identified, including one that encodes centrosome protein 4.1 associated protein (CPAP; also known as centromere protein J, CENPJ). CPAP is a large coiled-coil protein enriched at the centrosome, a structure that comprises two centrioles and surrounding pericentriolar material (PCM). CPAP depletion impairs centriole formation, whereas CPAP overexpression results in overly long centrioles. The mechanisms by which CPAP MCPH patient mutations affect brain development are not clear. Here, we identify CPAP protein domains crucial for its centriolar localization, as well as for the elongation and the formation of centrioles. Furthermore, we demonstrate that conditions that resemble CPAP MCPH patient mutations compromise centriole formation in tissue culture cells. Using adhesive micropatterns, we reveal that such defects correlate with a randomization of spindle position. Moreover, we demonstrate that the MCPH protein SCL/TAL1 interrupting locus (STIL) is also essential for centriole formation and for proper spindle position. Our findings are compatible with the notion that mutations in CPAP and STIL cause MCPH because of aberrant spindle positioning in progenitor cells during brain development.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Centriolos
/
Péptidos y Proteínas de Señalización Intracelular
/
Microcefalia
/
Proteínas Asociadas a Microtúbulos
/
Huso Acromático
Tipo de estudio:
Clinical_trials
/
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Cell Sci
Año:
2011
Tipo del documento:
Article
País de afiliación:
Suiza
Pais de publicación:
Reino Unido