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Abstract
Members of the ribonuclease A (RNase A) superfamily regulate various physiological processes. RNase A, the best-studied member of the RNase A superfamily, is widely expressed in different tissues, including brains. We unexpectedly found that RNase A can trigger proliferation of neuronal progenitor cells (NPC) both in vitro and in vivo. RNase A treatment induced cell proliferation in dissociated neuronal cultures and increased cell mass in neurosphere cultures. BrdU (5-Bromo-2'-Deoxyuridine) labeling confirmed the effect of RNase A on cell proliferation. Those dividing cells were Nestin- and SOX2-positive, suggesting that RNase A triggers NPC proliferation. The proliferation inhibitor Ara-C completely suppressed the effect of RNase A on NPC counts, further supporting that RNase A increases NPC number mainly by promoting proliferation. Moreover, we found that RNase A treatment increased ERK phosphorylation and blockade of the ERK pathway inhibited the effect of RNase A on NPC proliferation. Intracerebroventricular injection of RNase A into mouse brain increased the population of 5-ethynyl-2'-deoxyuridine (EdU) or BrdU-labeled cells in the subventricular zone. Those RNase A-induced NPCs were able to migrate into other brain areas, including hippocampus, amygdala, cortex, striatum, and thalamus. In conclusion, our study shows that RNase A promotes proliferation of NPCs via an ERK-dependent pathway and further diversifies the physiological functions of the RNase A family.
Highlights
The ribonuclease A (RNase A) superfamily consists of thirteen members in human (Cho et al, 2005; Gupta et al, 2013)
When we calculated the percentage of Nestin+ cells, we found that the population of Nestin+ cells increased from ∼20% in BSA groups to 60% in RNase A-treated groups (Figure 1B, right)
We unexpectedly found that RNase A can trigger neuronal progenitor cells (NPC) proliferation
Summary
The ribonuclease A (RNase A) superfamily consists of thirteen members in human (Cho et al, 2005; Gupta et al, 2013). The RNase A superfamily consists of secreted proteins that are expressed in a wide range of tissues, including brain (Gupta et al, 2013). They share similar primary sequences and a common disulfide-bonded tertiary conformation (Beintema, 1998). The mammalian RNase A superfamily is one of the most rapidly-evolving gene families in mammals (Cho et al, 2005), which may be relevant to the versatile functions of this family, including anti-bacterial and anti-viral activities (Rosenberg, 2008; Gupta et al, 2013; Rademacher et al, 2016), inhibition or promotion of tumor growth and RNase A Promotes Neurogenesis metastasis (Suzuki et al, 1999; Mironova et al, 2013, 2017; Chen et al, 2015; Attery et al, 2018; Wang et al, 2018), angiogenesis (Folkman and Klagsbrun, 1987; Gao and Xu, 2008; Sheng and Xu, 2016; Lyons et al, 2017), and cell proliferation (Li et al, 2013; Yu et al, 2017; Wang et al, 2018)
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