Novel role of Rac-Mid1 signaling in medial cerebellar development

• Published in: Development (Cambridge) Vol. 144; no. 10; pp. 1863 - 1875
• Main Authors: Nakamura, Takashi, Ueyama, Takehiko, Ninoyu, Yuzuru, Sakaguchi, Hirofumi, Choijookhuu, Narantsog, Hishikawa, Yoshitaka, Kiyonari, Hiroshi, Kohta, Masaaki, Sakahara, Mizuho, de Curtis, Ivan, Kohmura, Eiji, Hisa, Yasuo, Aiba, Atsu, Saito, Naoaki
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 15.05.2017
• Subjects: Animals; Apoptosis; Axonogenesis; Cell Differentiation - genetics; Cells, Cultured; Cerebellum; Cerebellum - embryology; Cerebellum - metabolism; Cyclin-dependent kinase inhibitor p27; Dendrites; Gallbladder; Granule cells; Haploinsufficiency; HEK293 Cells; Humans; Math1 protein; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Knockout; Multiprotein Complexes - physiology; Neurogenesis - genetics; Organogenesis - genetics; Proteins - genetics; Proteins - physiology; rac GTP-Binding Proteins - genetics; rac GTP-Binding Proteins - physiology; Rac1 protein; Signal transduction; Signal Transduction - genetics; Smooth muscle; TOR Serine-Threonine Kinases - physiology; Cerebellum; Opitz G/BBB syndrome; Cerebellar granule neurons; Midline 1; Rac; mTORC1
• ISSN: 0950-1991; 1477-9129
• DOI: 10.1242/dev.147900

Rac signaling impacts a relatively large number of downstream targets; however, few studies have established an association between Rac pathways and pathological conditions. In the present study, we generated mice with double knockout of and ( ) in cerebellar granule neurons (CGNs). We observed impaired tangential migration at E16.5, as well as numerous apoptotic CGNs at the deepest layer of the external granule layer (EGL) in the medial cerebellum of mice at P8. CGNs differentiated normally until expression of p27 and NeuN in the deep EGL at P5. Primary CGNs and cerebellar microexplants from mice exhibited impaired neuritogenesis, which was more apparent in Map2-positive dendrites. Such findings suggest that impaired tangential migration and final differentiation of CGNs have resulted in decreased cerebellum size and agenesis of the medial internal granule layer, respectively. Furthermore, Rac depleted/deleted cells exhibited decreased levels of Mid1 and impaired mTORC1 signaling. depletion in CGNs produced mild impairments in neuritogenesis and reductions in mTORC1 signaling. Thus, a novel Rac-signaling pathway (Rac1-Mid1-mTORC1) may be involved in medial cerebellar development.