Persson Laura, Witt Rochelle M, Galligan Meghan, Greer Paul L, Eisner Adriana, Pazyra-Murphy Maria F, Datta Sandeep R, Segal Rosalind A
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Neurobiology, Harvard Medical School, Boston, Massachusetts.
Dev Neurobiol. 2014 Dec;74(12):1255-67. doi: 10.1002/dneu.22202. Epub 2014 Jun 27.
The olfactory system relies on precise circuitry connecting olfactory sensory neurons (OSNs) and appropriate relay and processing neurons of the olfactory bulb (OB). In mammals, the exact correspondence between specific olfactory receptor types and individual glomeruli enables a spatially precise map of glomerular activation that corresponds to distinct odors. However, the mechanisms that govern the establishment and maintenance of the glomerular circuitry are largely unknown. Here we show that high levels of Sonic Hedgehog (Shh) signaling at multiple sites enable refinement and maintenance of olfactory glomerular circuitry. Mice expressing a mutant version of Shh (Shh(Ala/Ala)), with impaired binding to proteoglycan co-receptors, exhibit disproportionately small olfactory bulbs containing fewer glomeruli. Notably, in mutant animals the correspondence between individual glomeruli and specific olfactory receptors is lost, as olfactory sensory neurons expressing different olfactory receptors converge on the same glomeruli. These deficits arise at late stages in post-natal development and continue into adulthood, indicating impaired pruning of erroneous connections within the olfactory bulb. In addition, mature Shh(Ala/Ala) mice exhibit decreased proliferation in the subventricular zone (SVZ), with particular reduction in neurogenesis of calbindin-expressing periglomerular cells. Thus, Shh interactions with proteoglycan co-receptors function at multiple locations to regulate neurogenesis and precise olfactory connectivity, thereby promoting functional neuronal circuitry.
嗅觉系统依赖于连接嗅觉感觉神经元（OSN）与嗅球（OB）中适当的中继和处理神经元的精确神经回路。在哺乳动物中，特定嗅觉受体类型与单个嗅小球之间的确切对应关系使得嗅小球激活的空间精确图谱能够对应于不同的气味。然而，控制嗅小球神经回路建立和维持的机制在很大程度上尚不清楚。在这里，我们表明多个位点的高水平音猬因子（Shh）信号传导能够优化和维持嗅觉嗅小球神经回路。表达Shh突变体版本（Shh（Ala/Ala））且与蛋白聚糖共受体结合受损的小鼠，其嗅球异常小，包含的嗅小球数量也更少。值得注意的是，在突变动物中，单个嗅小球与特定嗅觉受体之间的对应关系丧失，因为表达不同嗅觉受体的嗅觉感觉神经元会汇聚到同一个嗅小球上。这些缺陷出现在出生后发育的后期，并持续到成年期，表明嗅球内错误连接的修剪受损。此外，成熟的Shh（Ala/Ala）小鼠在脑室下区（SVZ）的增殖减少，特别是表达钙结合蛋白的球周细胞的神经发生显著减少。因此，Shh与蛋白聚糖共受体的相互作用在多个位置发挥作用，以调节神经发生和精确的嗅觉连接，从而促进功能性神经元回路的形成。
