Bradykinin promotes neuron-generating division of neural progenitor cells through ERK activation

Abstract

During brain development, cells proliferate, migrate and differentiate in highly accurate patterns. In this context, published results indicate that bradykinin functions in neural fate determination, favoring neurogenesis and migration. However, mechanisms underlying bradykinin function are yet to be explored. Our findings indicate a previously unidentified role for bradykinin action in inducing neurongenerating division in vitro and in vivo, given that bradykinin lengthened the G 1 -phase of the neural progenitor cells (NPC) cycle and increased TIS21 (also known as PC3 and BTG2) expression in hippocampus from newborn mice. This role, triggered by activation of the kinin-B2 receptor, was conditioned by ERK1/2 activation. Moreover, immunohistochemistry analysis of hippocampal dentate gyrus showed that the percentage of Ki67 + cells markedly increased in bradykinin-treated mice, and ERK1/2 inhibition affected this neurogenic response. The progress of neurogenesis depended on sustained ERK phosphorylation and resulted in ERK1/2 translocation to the nucleus in NPCs and PC12 cells, changing expression of genes such as Hes1 and Ngn2 (also known as Neurog2). In agreement with the function of ERK in integrating signaling pathways, effects of bradykinin in stimulating neurogenesis were reversed following removal of protein kinase C (PKC)-mediated sustained phosphorylation.

Impaired adult hippocampal neurogenesis in Alzheimer’s disease is mediated by microRNA-132 deficiency and can be restored by microRNA-132 replacement

“…This approach revealed a novel miR-132-specific molecular signature consisting of DOCK1, EPHB3, BTG2, CAMK1 and RAC1 , all of which have reported roles in neuronal differentiation and function (Fortin et al, 2010; Goold and Nicoll, 2010; Pillat et al, 2016; Theus et al, 2010; Vadodaria et al, 2013; Yang et al, 2012). Dock1, Ephb3, Camk1 and Rac1 have additionally been implicated in AD (Aguilar et al, 2017; Becker et al, 2014; Overk and Masliah, 2014; Riascos et al, 2014), while all five proteins have been associated with the immune response in a variety of cells (D’Ambrosi et al, 2014; Goold and Nicoll, 2010; Guo et al, 2013; Naskar et al, 2014; Pillat et al, 2016; Theus et al, 2010; Yuniati et al, 2018). Interestingly, miR-132 knockdown also repressed the running-induced increase of Bdnf , a key neurotrophic factor contributing to the fitness of the niche and the neurogenic potential.…”

Lack of dcf1 leads to neuronal migration delay, axonal swollen and autism-related deficits

“…ERK is the most downstream protein kinase of the canonical Ras-Raf-MEK-ERK cascade that can be suppressed by Raf kinase inhibitory protein, PEBP1 (Pyo et al, 2018). ERK signaling is critical in early neurogenesis (Ye et al, 2016); it directs self-renewal, division and differentiation of neural progenitor cells (Dee et al, 2016;Pillat et al, 2016). ERK signaling is dispensable for morphological and survival of large Ctip2 + neurons in layer 5 (Xing et al, 2016).…”

Kinin B2-Receptor in human iPSC differentiation into cardiomyocytes

“…Our group has studied, over the years, the mechanisms through which KKS (kininkallikrein system and its receptors) modulates key cellular processes in neurons, such as cell proliferation (83) and differentiation (74,76,77,79,135). Moreover, additional unpublished data from our group (80) and by others (102) suggests that BK aids skeletal muscle regeneration and differentiation.…”

“…In addition to being related to cell proliferation and survival, our group has thoroughly studied the role of kinin receptors in in vitro cell differentiation: studies using human and mice embryonic cells show that, following retinoic acid induction, embryonic bodies undergo neuronal differentiation, expressing augmented levels of both BK and functional B2R towards the end of the differentiation stimulus (74,75,77,79). Moreover, B2R…”

“…(Fig.10c), and that BK doses as low as 1nM can lead to a 14-fold increase in the cellular fluorescence (p<0.001). Previous works from our laboratory groups have used 1µM BK to induce neural differentiation (75,77,79). As this peptide is not very stable in solution (half-life = 30s (85)) and aiming to induce the greatest possible response, we decided to first test the effect of 10µM BK on TNNI1 and TNNI3 gene expression and ssTnI/cTnI protein expression.…”