ERK1/2 Signalling Pathway Regulates Tubulin-Binding Cofactor B Expression and Affects Astrocyte Process Formation after Acute Foetal Alcohol Exposure

Abstract

Foetal alcohol spectrum disorders (FASDs) are a spectrum of neurological disorders whose neurological symptoms, besides the neuronal damage caused by alcohol, may also be associated with neuroglial damage. Tubulin-binding cofactor B (TBCB) may be involved in the pathogenesis of FASD. To understand the mechanism and provide new insights into the pathogenesis of FASD, acute foetal alcohol exposure model on astrocytes was established and the interference experiments were carried out. First, after alcohol exposure, the nascent astrocyte processes were reduced or lost, accompanied by the absence of TBCB expression and the disruption of microtubules (MTs) in processes. Subsequently, TBCB was silenced with siRNA. It was severely reduced or lost in nascent astrocyte processes, with a dramatic reduction in astrocyte processes, indicating that TBCB plays a vital role in astrocyte process formation. Finally, the regulating mechanism was studied and it was found that the extracellular signal-regulated protease 1/2 (ERK1/2) signalling pathway was one of the main pathways regulating TBCB expression in astrocytes after alcohol injury. In summary, after acute foetal alcohol exposure, the decreased TBCB in nascent astrocyte processes, regulated by the ERK1/2 signalling pathway, was the main factor leading to the disorder of astrocyte process formation, which could contribute to the neurological symptoms of FASD.

Innovation at the Intersection: Emerging Translational Research in Neurology and Psychiatry

“…The third paper investigates the role of the extracellular-signal-regulated kinase (ERK)1/2 signaling pathway in regulating the tubulin-binding cofactor B (TBCB) expression and affecting the astrocyte process formation after acute fetal alcohol exposure [87]. ERK1/2 is a key kinase that mediates various cellular processes, such as proliferation, differentiation, and survival.…”

Innovation at the Intersection: Emerging Translational Research in Neurology and Psychiatry

“…The third paper investigates the role of the extracellular signal-regulated kinase (ERK)1/2 signaling pathway in regulating the tubulin-binding cofactor B (TBCB) expression and affecting the astrocyte process formation after acute fetal alcohol exposure [79]. ERK1/2 is a key kinase that mediates various cellular processes, such as proliferation, differentiation, and survival.…”

Neuroimmune Interactions in Fetal Alcohol Spectrum Disorders: Potential Therapeutic Targets and Intervention Strategies

“…In cultured astrocytes, ethanol promotes the activation of pro-inflammatory interleukin 1 receptor (IL-1R)-associated kinase, extracellular signal-regulated protein kinase 1/2 (ERK1/2), p38, and Jun N-terminal kinases (JNK) and the production of ROS [ 64 , 65 , 66 , 67 ]. Activated pro-inflammatory signaling pathways then increase the production of pro-inflammatory molecules such as IL-1β, iNOS, and COX2 in cultured astrocytes [ 53 , 57 ].…”

“…For example, upon stimulation with lipopolysaccharide (LPS), histone methyltransferase activity is increased, leading to an increase in tri-methylation of histone H3 lysine 27 (H3K27) and pro-inflammatory gene nuclear factor-κB (Nfkb1) levels in mouse microglia [ 64 , 65 ]. Also, the activation of TLR4 signaling by LPS is shown to increase tet methylcytosine dioxygenase 2 (TET2) levels and stimulate the expression of pro-inflammatory cytokines in mouse microglia [ 66 ]. TET2 has been shown to facilitate the oxidative conversion of 5-methylcytosine (5 mC) to 5-hydroxymetylcytosine (5 hmC) [ 77 ].…”