Todd Krysti L, Baker Kasey L, Eastman Matthew B, Kolling Frederick W, Trausch Alexandra G, Nelson Craig E, Conover Joanne C
Department of Physiology and Neurobiology and.
Department of Molecular and Cell Biology, University of Connecticut, Storrs, Connecticut 06269.
J Neurosci. 2017 Mar 22;37(12):3331-3341. doi: 10.1523/JNEUROSCI.3738-16.2017. Epub 2017 Mar 3.
Significant migration cues are required to guide and contain newly generated rodent subventricular zone (SVZ) neuroblasts as they transit along the lateral ventricles and then through the anterior forebrain to their ultimate site of differentiation in the olfactory bulbs (OBs). These cues enforce strict neuroblast spatial boundaries within the dense astroglial meshwork of the SVZ and rostral migratory stream (RMS), yet are permissive to large-scale neuroblast migration. Therefore, the molecular mechanisms that define these cues and control dynamic interactions between migratory neuroblasts and surrounding astrocytes are of particular interest. We found that deletion of EphA4 and specifically ablation of EphA4 kinase activity resulted in misaligned neuroblasts and disorganized astrocytes in the RMS/SVZ, linking EphA4 forward signaling to SVZ and RMS spatial organization, orientation, and regulation. In addition, within a 3 week period, there was a significant reduction in the number of neuroblasts that reached the OB and integrated into the periglomerular layer, revealing a crucial role for EphA4 in facilitating efficient neuroblast migration to the OB. Single-cell analysis revealed that and its binding partners are expressed by subpopulations of neuroblasts and astrocytes within the SVZ/RMS/OB system resulting in a cell-specific mosaic, suggesting complex EphA4 signaling involving both homotypic and heterotypic cell-cell interactions. Together, our studies reveal a novel molecular mechanism involving EphA4 signaling that functions in stem cell niche organization and ultimately neuroblast migration in the anterior forebrain. The subventricular zone neurogenic stem cell niche generates highly migratory neuroblasts that transit the anterior forebrain along a defined pathway to the olfactory bulb. Postnatal and adult brain organization dictates strict adherence to a narrow migration corridor. Subventricular zone neuroblasts are aligned in tightly bundled chains within a meshwork of astrocytes; however, the cell-cell cues that organize this unique, cell-dense migration pathway are largely unknown. Our studies show that forward signaling through the EphA4 tyrosine kinase receptor, mediated by ephrins expressed by subpopulations of neuroblasts and astrocytes, is required for compact, directional organization of neuroblasts and astrocytes within the pathway and efficient transit of neuroblasts through the anterior forebrain to the olfactory bulb.
在新生啮齿动物的脑室下区（SVZ）神经母细胞沿着侧脑室迁移，然后穿过前脑前部到达其在嗅球（OB）中最终分化位点的过程中，需要重要的迁移线索来引导和限制它们。这些线索在SVZ和吻侧迁移流（RMS）密集的星形胶质网络内强化严格的神经母细胞空间边界，但又允许大规模的神经母细胞迁移。因此，确定这些线索并控制迁移神经母细胞与周围星形胶质细胞之间动态相互作用的分子机制尤其令人关注。我们发现，EphA4的缺失以及EphA4激酶活性的特异性缺失导致RMS/SVZ中神经母细胞排列不齐和星形胶质细胞紊乱，将EphA4正向信号传导与SVZ和RMS的空间组织、定向及调节联系起来。此外，在3周内，到达OB并整合到肾小球周围层的神经母细胞数量显著减少，这揭示了EphA4在促进神经母细胞有效迁移到OB中的关键作用。单细胞分析显示， 及其 结合伙伴由SVZ/RMS/OB系统内神经母细胞和星形胶质细胞亚群表达，形成细胞特异性镶嵌，表明涉及同型和异型细胞间相互作用的复杂EphA4信号传导。总之，我们的研究揭示了一种涉及EphA4信号传导的新分子机制，该机制在干细胞生态位组织中发挥作用，并最终在前脑前部的神经母细胞迁移中起作用。脑室下区神经源性干细胞生态位产生高度迁移的神经母细胞，这些神经母细胞沿着确定的路径穿过前脑前部到达嗅球。出生后和成年期的脑组织要求严格遵循狭窄的迁移通道。脑室下区神经母细胞在星形胶质细胞网络内排列成紧密捆绑的链状；然而，组织这种独特的、细胞密集的迁移途径的细胞间线索在很大程度上尚不清楚。我们的研究表明，由神经母细胞和星形胶质细胞亚群表达的ephrin介导通过EphA4酪氨酸激酶受体的正向信号传导，对于神经母细胞和星形胶质细胞在该途径内的紧密、定向组织以及神经母细胞有效穿过前脑前部到达嗅球是必需的。
