Neural tube defects and impaired neural progenitor cell proliferation in Gβ1‐deficient mice

Abstract

Heterotrimeric G proteins are well known for their roles in signal transduction downstream of G protein–coupled receptors (GPCRs), and both Gα subunits and tightly associated Gβγ subunits regulate downstream effector molecules. Compared to Gα subunits, the physiological roles of individual Gβ and Gγ subunits are poorly understood. In this study, we generated mice deficient in the Gβ1 gene and found that Gβ1 is required for neural tube closure, neural progenitor cell proliferation, and neonatal development. About 40% Gβ1−/− embryos developed neural tube defects (NTDs) and abnormal actin organization was observed in the basal side of neuroepithelium. In addition, Gβ1−/− embryos without NTDs showed microencephaly and died within 2 days after birth. GPCR agonist‐induced ERK phosphorylation, cell proliferation, and cell spreading, which were all found to be regulated by Gαi and Gβγ signaling, were abnormal in Gβ1−/− neural progenitor cells. These data indicate that Gβ1 is required for normal embryonic neurogenesis. Developmental Dynamics 239:1089–1101, 2010. © 2010 Wiley‐Liss, Inc.

The Expanding Roles of GβγSubunits in G Protein–Coupled Receptor Signaling and Drug Action

“…To date, of the four similar Gb subunits, only Gb 1 has been knocked out in mice. Interestingly, 40% of Gb 1 2/2 mice exhibit neural tube defects resulting in embryonic lethality, whereas the knockout mice that do not exhibit this phenotype develop microencephaly and die perinatally (Okae and Iwakura, 2010). Additional defects in Gb 1 2/2 mice without neural tube defects include abnormal suckling behavior and respiratory defects.…”

Gβ 4 γ 1 as a modulator of M3 muscarinic receptor signalling and novel roles of Gβ 1 subunits in the modulation of cellular signalling

“…Although a number of studies have also examined the specific roles of individual Gβ and Gγ subunits, we still do not have a clear view of their individual functions. Functions for individual Gβ and Gγ subunits have been attributed using antisense approaches and the roles they play in receptor signalling pathways as well as embryonic development have been characterized in animal knockout models [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. Gβ [1][2][3][4] subunits share 78-88% identity over their approximately 340 amino acid sequences (reviewed in [2,19]).…”

Heterotrimeric G Proteins and the Regulation of Microtubule Assembly

“…The involvement of Gβγ in neuronal development and differentiation has been previously shown [68,89]. Gβ1-deficient mice have been shown to have neural tube defects [94], and Gβ5-knockout mice have been shown to display abnormal behavior and develop multiple brain abnormalities [95]. It has also been shown that impaired Gβγ signaling promotes neurogenesis in the developing neocortex and increased neuronal differentiation of progenitor cells [68].…”

“…More recently, using biochemical and immunofluorescence analysis, it has been demonstrated that Gβγ-MT interactions and modulation of MT assembly is critical for NGF-induced neuronal differentiation of PC12 cells [94]. To address this, PC12 cells were treated with NGF over the course of three days to allow for neuronal differentiation.…”

“…Microtubules (MTs) and soluble tubulin (ST) fractions were extracted using a microtubule-stabilizing buffer. The interaction of Gβγ with MT and ST fractions was analyzed by coimmunoprecipitating tubulin-Gβγ complex using a Gβ-specific antibody (rabbit polyclonal anti-Gβ) or a mouse monoclonal anti-α tubulin antibody and determining tubulin and Gβγ immunoreactivity in the complex [94]. Gβγ-MT interaction was significantly increased (2-3 fold) in NGF-treated cells.…”