Abstract
The DOC-2/DAB2 interactive protein (DAB2IP) is a new member of the Ras GTPase–activating protein family. Recent studies have shown that, in addition to its tumor suppressive role in various tumors, DAB2IP also plays an important role in regulating neuronal migration and positioning during brain development. In this study, we determined the roles of DAB2IP in the neuronal differentiation of human mesenchymal stem cells (hMSCs). We found that lentiviral short hairpin RNA (shRNA)-mediated knockdown of DAB2IP promoted the mesenchymal-to-neuroepithelial stem cell transition (MtNeST) and neuronal differentiation, which were accompanied by a reduction of cell proliferation but not apoptosis or cellular senescence. This suggests that DAB2IP plays an important role in the neuronal induction of hMSCs. Moreover, our finding that reduction of glycogen synthase kinase 3 beta (GSK3β) activity upon LiCl pretreatment inhibited both the MtNeST and production of MAP2-positive cells upon DAB2IP knockdown suggests that this transition is most likely mediated by regulation of the GSK3β signaling pathway. Our study demonstrates that DAB2IP participates in the first step of neuron induction of hMSCs, which implies a potentially important role for DAB2IP in the MtNeST during neurogenesis.
Highlights
Deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/ DAB2) interactive protein (DAB2IP), known as apoptosis signal-regulating kinase–interacting protein-1, is a new member of the Ras GTPase-activating protein family [1]
Our laboratory and others have reported that human mesenchymal stem cells (hMSCs) can be induced to differentiate into functional neuronal cell with electrophysiological properties using neuronal induction medium (NIM) containing 3isobutyl-1-methyl-xanthine [22,23,30]
Expression of the neuronal markers Tuj-1, microtubule-associated protein 2 (MAP2), and neuronspecific enolase (NSE) was induced in neurons differentiated from 3A6-hMSCs (3A6-hMSC-differentiated neurons) (Figure 1A-C)
Summary
Deletion of ovarian carcinoma 2/disabled homolog 2 (DOC-2/ DAB2) interactive protein (DAB2IP), known as apoptosis signal-regulating kinase–interacting protein-1, is a new member of the Ras GTPase-activating protein family [1]. Previous studies of DAB2IP have unveiled its tumor suppressor role in various types of cancers [1,2,3,4,5]. DAB2IP can inhibit cell survival by suppressing the phosphatidyl inositol 3-kinase (PI3K)-Akt kinase signaling pathway and can promote tumor necrosis factors mediated apoptosis by activating the apoptosis signal–. In addition to its tumor suppressor role, DAB2IP plays an important role in regulating brain development. Dab2ip function in the developing mouse brain is likely related to its interacting proteins, Drosophila disabled homolog 1 and 2
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