Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Regulates Neurite Outgrowth Through the Activation of Akt/mTOR and Erk/mTOR Signaling Pathways

Abstract

Neurite outgrowth is essential for brain development and the recovery of brain injury and neurodegenerative diseases. In this study, we examined the role of the neurotrophic factor MANF in regulating neurite outgrowth. We generated MANF knockout (KO) neuro2a (N2a) cell lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and demonstrated that MANF KO N2a cells failed to grow neurites in response to RA stimulation. Using MANF siRNA, this finding was confirmed in human SH-SY5Y neuronal cell line. Nevertheless, MANF overexpression by adenovirus transduction or addition of MANF into culture media facilitated the growth of longer neurites in RA-treated N2a cells. MANF deficiency resulted in inhibition of Akt, Erk, mTOR, and P70S6, and impaired protein synthesis. MANF overexpression on the other hand facilitated the growth of longer neurites by activating Akt, Erk, mTOR, and P70S6. Pharmacological blockade of Akt, Erk or mTOR eliminated the promoting effect of MANF on neurite outgrowth. These findings suggest that MANF positively regulated neurite outgrowth by activating Akt/mTOR and Erk/mTOR signaling pathways.

Transection injury differentially alters the proteome of the human sural nerve

“…After injury in mice, GDNF peaks around 7 days, and BDNF levels peak around 2–3 weeks [ 43 ]. Trophic factors involved in neurite outgrowth, cytoprotection, and neuronal survival such as mesencephalic astrocyte-derived neurotrophic factor (MANF) have also been reported to increase after peripheral nerve injury similar to the upregulation we observed in our analyses [ 48 , 49 ].…”

1800 MHz Radiofrequency Electromagnetic Field Impairs Neurite Outgrowth Through Inhibiting EPHA5 Signaling

“…These pathways were directly related to neurite development. Also, the enriched items included some pathways which have been demonstrated closely related to neurite development, such as the PI3K-AKT signaling pathway (Zhao et al, 2020), mTOR signaling pathway (Wen et al, 2020), cGMP-PKG signaling pathway (Sun et al, 2020), thyroid hormone signaling pathway (Poddar et al, 1996), and calcium signaling pathway (Zhao et al, 2019; Figure 2E).…”

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF): An Emerging Therapeutic Target for Neurodegenerative Disorders

“…Several studies also showed MANF’s ability to induce neurite outgrowth. For example, MANF was shown to promote neurite outgrowth in DA neurons and N2a cells [ 2 , 65 ]. Additionally, MANF was shown to be essential for neurite extension in the developing mouse cortex.…”