Deletion of the \u03b1 subunit of the heterotrimeric Go protein impairs cerebellar cortical development in mice

Hye Lim Cha,Sung-Soo Kim,Jung-Mi Choi,Narayan Bashyal,Lutz Birnbaumer,Haeyoung Suh-Kim,Huy-Hyen Oh

doi:10.1186/s13041-019-0477-9

Abstract

Go is a member of the pertussis toxin-sensitive Gi/o family. Despite its abundance in the central nervous system, the precise role of Go remains largely unknown compared to other G proteins. In the present study, we explored the functions of Go in the developing cerebellar cortex by deleting its gene, Gnao. We performed a histological analysis with cerebellar sections of adult mice by cresyl violet- and immunostaining. Global deletion of Gnao induced cerebellar hypoplasia, reduced arborization of Purkinje cell dendrites, and atrophied Purkinje cell dendritic spines and the terminal boutons of climbing fibers from the inferior olivary nucleus. These results indicate that Go-mediated signaling pathway regulates maturation of presynaptic parallel fibers from granule cells and climbing fibers during the cerebellar cortical development.

Highlights

When G-protein coupled receptors (GPCRs) bind their cognate ligands, their respective heterotrimeric GTP binding proteins (G-proteins) are activated, inducing the dissociation of Gα from Gβγ
Cresyl violet staining showed that the lack of GTP-binding Protein alpha subunit of Go (Gαo) does not alter the overall lobulation of the cerebellar cortex; the only significant difference we observed in Gnao−/− mice was a 62% reduction in the depth of the intercrural fissure between lobules VI and VII [37] (0.25 ± 0.02 mm in Gnao+/+ mice; 0.10 ± 0.04 mm in Gnao−/− mice; n = 3 mice for each genotype≥P25; *p < 0.05; arrows in Fig. 1ab, and g)
Since the thickness and shape of the granule cell layer (GCL) varies among the folia, we compared the total area occupied by the GCL in Gnao−/− mice to that of their wild-type littermates (Additional file 1)

Summary

Introduction

When G-protein coupled receptors (GPCRs) bind their cognate ligands, their respective heterotrimeric GTP binding proteins (G-proteins) are activated, inducing the dissociation of Gα from Gβγ. Specificity of GPCR signal transduction is determined by the functions of the specific Gα subunits because all G-proteins share a pool of Gβγ subunits. Gα subunits are classified into four subfamilies: Gαs, Gαi/o, Gαq/11, and Gα12/13. 16 different mammalian Gα subunits have been identified [1, 2]. Go belongs to the pertussis toxin-sensitive Gi/o family, the α subunits of which share 71% amino acid sequence homology. Gαi proteins are ubiquitously expressed and well-studied. They inhibit adenylyl cyclase (AC) directly and reduce intracellular cyclic AMP (cAMP) levels [3].

Methods

Results

Conclusion