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Abstract
Neural progenitor cells (NPCs) are self-renewing cells that give rise to the major cells in the nervous system and are considered to be the possible cell of origin of glioblastoma. The gap junction protein connexin43 (Cx43) is expressed by NPCs, exerting channel-dependent and -independent roles. We focused on one property of Cx43—its ability to inhibit Src, a key protein in brain development and oncogenesis. Because Src inhibition is carried out by the sequence 266–283 of the intracellular C terminus in Cx43, we used a cell-penetrating peptide containing this sequence, TAT-Cx43266–283, to explore its effects on postnatal subventricular zone NPCs. Our results show that TAT-Cx43266–283 inhibited Src activity and reduced NPC proliferation and survival promoted by epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2). In differentiation conditions, TAT-Cx43266–283 increased astrocyte differentiation at the expense of neuronal differentiation, which coincided with a reduction in Src activity and β-catenin expression. We propose that Cx43, through the region 266–283, reduces Src activity, leading to disruption of EGF and FGF-2 signaling and to down-regulation of β-catenin with effects on proliferation and differentiation. Our data indicate that the inhibition of Src might contribute to the complex role of Cx43 in NPCs and open new opportunities for further research in gliomagenesis.
Highlights
Neural progenitor cells (NPCs) are a heterogeneous population of self-renewing and multipotent cells that give rise to the three major cell types in the developing central nervous system: neurons, astrocytes, and oligodendrocytes [1,2]
We evaluated the effect of TAT-Cx43266–283 on the size of the neurospheres formed when neurosphere-derived NPCs were mechanically dissociated and cultured with 20 ng/mL epidermal growth factor (EGF) and 10 ng/mL fibroblast growth factor-2 FGF-2, i.e., in proliferation conditions
Because Src is involved in the signaling pathway evoked by EGF and FGF-2 [43,44], and BTeAcTa-uCsxe4S3r2c66i–s28in3 vroeldvuedceisn Sthrce saicgtnivailtiynginpaathswtroacyyetevsokaenddbyinEGglFioamnad FstGeFm-2c[e4l3ls,44i]n, vanitdroTaAnTdiCnxv4i3v2o66-2[8432r,e4d5u],cweseSarcimacetdivtiotycionnafisrtmrocwytheesthanerd Sinrcgalicotmiviatysteismalcseollsinihnivbiittreod abnydTinATv-iCvox4[34226,64–52]8,3wine aimed to confirm whether Src activity is inhibited by TAT-Cx43266-283 in PC NPCs
Summary
Neural progenitor cells (NPCs) are a heterogeneous population of self-renewing and multipotent cells that give rise to the three major cell types in the developing central nervous system: neurons, astrocytes, and oligodendrocytes [1,2]. NPCs persist in the postnatal and adult brain in two specific regions: the subventricular zone (SVZ) of the lateral ventricles and the dentate gyrus of the hippocampus [3]. In addition to their physiological role, there is strong evidence showing that NPCs from the SVZ could be the cell of origin of glioblastoma, the most common and devastating primary brain tumor [4,5,6,7,8,9]. Multiple mechanisms and molecules have been reported to be involved in the control of NPC survival, proliferation, migration, and differentiation towards neurons, astrocytes, and oligodendrocytes. Several reports have indicated that intercellular communication through GJs plays an important role in the maintenance of NPC proliferation [15], survival [13,16], and pluripotency [17]
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