Neural Engineering Center, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, 44106, USA.
Advanced Platform Technology Center, L. Stokes Cleveland VA Medical Center, Rehab. R&D, 10701 East Blvd. Mail Stop 151 AW/APT, Cleveland, OH, 44106, USA.
Sci Rep. 2019 Nov 22;9(1):17402. doi: 10.1038/s41598-019-53192-4.
Sonic hedgehog (Shh) is a multifunctional signaling protein governing pattern formation, proliferation and cell survival during embryogenesis. In the adult brain, Shh has neurotrophic function and is implicated in hippocampal neurogenesis but the cellular source of Shh in the hippocampus remains ill defined. Here, we utilize a gene expression tracer allele of Shh (Shh-nlacZ) which allowed the identification of a subpopulation of hilar neurons known as mossy cells (MCs) as a prominent and dynamic source of Shh within the dentate gyrus. AAV-Cre mediated ablation of Shh in the adult dentate gyrus led to a marked degeneration of MCs. Conversely, chemical stimulation of hippocampal neurons using the epileptogenic agent kainic acid (KA) increased the number of Shh MCs indicating that the expression of Shh by MCs confers a survival advantage during the response to excitotoxic insults. In addition, ablation of Shh in the adult dentate gyrus led to increased neural precursor cell proliferation and their migration into the subgranular cell layer demonstrating that MCs-generated Shh is a key modulator of hippocampal neurogenesis.
Sonic hedgehog (Shh) 是一种多功能信号蛋白，在胚胎发生过程中调节形态发生、增殖和细胞存活。在成年大脑中，Shh 具有神经营养功能，并与海马神经发生有关，但海马中的 Shh 细胞来源仍未明确。在这里，我们利用 Shh 的基因表达示踪剂等位基因（Shh-nlacZ），该基因可以鉴定出一种称为苔藓细胞（MCs）的海马回神经元亚群，作为齿状回内 Shh 的主要和动态来源。AAV-Cre 介导的成年齿状回 Shh 消融导致 MCs 明显退化。相反，使用致癫痫剂海人酸（KA）化学刺激海马神经元增加了 Shh MCs 的数量，表明 MCs 表达 Shh 在对兴奋性损伤的反应中赋予了生存优势。此外，成年齿状回 Shh 的消融导致神经前体细胞增殖增加，并迁移到颗粒下细胞层，表明 MC 产生的 Shh 是海马神经发生的关键调节剂。
