Spindle Misorientation of Cerebral and Cerebellar Progenitors Is a Mechanistic Cause of Megalencephaly

• Published in: Stem cell reports 2017-10, Vol.9 (4), p.1071-1080
• Main Authors: Li, Huaibiao, Kroll, Torsten, Moll, Jürgen, Frappart, Lucien, Herrlich, Peter, Heuer, Heike, Ploubidou, Aspasia
• Format: Article
• Language: English
• Subjects: Animals; brain development; Cell Differentiation; Cell Division; cerebellar granule cell precursor; Cerebellum - cytology; cerebellum differentiation; cerebral cortex; Cerebral Cortex - cytology; cerebral neuroprogenitor; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Gene Expression; Hyaluronan Receptors - genetics; Hyaluronan Receptors - metabolism; Megalencephaly - etiology; Megalencephaly - pathology; Mice; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurogenesis; neuronal progenitor; Organogenesis; oriented division; Protein Transport; RHAMM; Spindle Apparatus - metabolism
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2017.08.013

Misoriented division of neuroprogenitors, by loss-of-function studies of centrosome or spindle components, has been linked to the developmental brain defects microcephaly and lissencephaly. As these approaches also affect centrosome biogenesis, spindle assembly, or cell-cycle progression, the resulting pathologies cannot be attributed solely to spindle misorientation. To address this issue, we employed a truncation of the spindle-orienting protein RHAMM. This truncation of the RHAMM centrosome-targeting domain does not have an impact on centrosome biogenesis or on spindle assembly in vivo. The RHAMM mutants exhibit misorientation of the division plane of neuroprogenitors, without affecting the division rate of these cells, resulting against expectation in megalencephaly associated with cerebral cortex thickening, cerebellum enlargement, and premature cerebellum differentiation. We conclude that RHAMM associates with the spindle of neuroprogenitor cells via its centrosome-targeting domain, where it regulates differentiation in the developing brain by orienting the spindle. [Display omitted] •Cerebral cortex apical progenitors (APs) and cerebellar GCPs exhibit planar division•Spindle-associated RHAMM orients the division plane of these neuroprogenitors•Excessive apicobasal division of APs causes cerebral cortex thickening•Decreased planar division of GCPs causes cerebellum enlargement Ploubidou and colleagues assess the impact of misorientation of the mitotic spindle of neuronal progenitor cells on brain development. They employ a spindle misorientation model expressing truncated RHAMM, exhibiting no centrosome biogenesis or spindle assembly defects in vivo. The data demonstrate that spindle misorientation in cerebellum and cerebrum neuroprogenitors results in megalencephaly and that RHAMM regulates differentiation in the developing brain.