Hooper Kelsey M, Lundquist Erik A
University of Kansas, Department of Molecular Biosciences, Program in Molecular, Cellular, and Developmental Biology.
bioRxiv. 2024 Apr 23:2024.04.23.590737. doi: 10.1101/2024.04.23.590737.
Recent studies in vertebrates and have reshaped models of how the axon guidance cue UNC-6/Netrin functions in dorsal-ventral axon guidance, which was traditionally thought to form a ventral-to-dorsal concentration gradient that was actively sensed by growing axons. In the vertebrate spinal cord, floorplate Netrin1 was shown to be largely dispensable for ventral commissural growth. Rather, short range interactions with Netrin1 on the ventricular zone radial glial stem cells was shown to guide ventral commissural axon growth. In , analysis of dorsally-migrating growth cones during outgrowth has shown that growth cone polarity of filopodial extension is separable from the extent of growth cone protrusion. Growth cones are first polarized by UNC-6/Netrin, and subsequent regulation of protrusion by UNC-6/Netrin is based on this earlier-established polarity (the Polarity/Protrusion model). In both cases, short-range or even haptotactic mechanisms are invoked: in vertebrate spinal cord, interactions of growth cones with radial glia expressing Netrin-1; and in a potential close-range interaction that polarizes the growth cone. To explore potential short-range and long-range functions of UNC-6/Netrin, a potentially membrane-anchored transmembrane UNC-6 (UNC-6(TM)) was generated by genome editing. was hypomorphic for dorsal VD/DD axon pathfinding, indicating that it retained some function. Polarity of VD growth cone filopodial protrusion was initially established in , but was lost as the growth cones migrated away from the source in the ventral nerve cord. In contrast, ventral guidance of the AVM and PVM axons was equally severe in and . Together, these results suggest that retains short-range functions but lacks long-range functions. Finally, ectopic expression from non-ventral sources could rescue dorsal and ventral guidance defects in and . Thus, a ventral directional source of UNC-6 was not required for dorsal-ventral axon guidance, and UNC-6 can act as a permissive, not instructive, cue for dorsal-ventral axon guidance. Possibly, UNC-6 is a permissive signal that activates cell-intrinsic polarity; or UNC-6 acts with another signal that is required in a directional manner. In either case, the role of UNC-6 is to polarize the pro-protrusive activity of UNC-40/DCC in the direction of outgrowth.
最近在脊椎动物中的研究重塑了轴突导向因子UNC-6/Netrin在背腹轴突导向中发挥作用的模型，传统观点认为它形成了一个从腹侧到背侧的浓度梯度，生长中的轴突能主动感知该梯度。在脊椎动物脊髓中，底板Netrin1对腹侧连合生长在很大程度上是可有可无的。相反，与室管膜区放射状胶质干细胞上的Netrin1进行短程相互作用被证明可引导腹侧连合轴突生长。在[具体生物名称未给出]中，对生长过程中背向迁移的生长锥的分析表明，丝状伪足延伸的生长锥极性与生长锥突出程度是可分离的。生长锥首先由UNC-6/Netrin极化，随后UNC-6/Netrin对突出的调节基于这种早期建立的极性（极性/突出模型）。在这两种情况下，都涉及短程甚至触觉机制：在脊椎动物脊髓中，生长锥与表达Netrin-1的放射状胶质细胞相互作用；在[具体生物名称未给出]中，一种潜在的近距离相互作用使生长锥极化。为了探索UNC-6/Netrin的潜在短程和长程功能，通过基因组编辑产生了一种可能膜锚定的跨膜UNC-6（UNC-6(TM)）。[具体生物名称未给出]在背侧VD/DD轴突寻路方面是亚效的，表明它保留了一些功能。VD生长锥丝状伪足突出的极性最初在[具体生物名称未给出]中建立，但随着生长锥从腹侧神经索中的[具体生物名称未给出]源迁移而丧失。相比之下，AVM和PVM轴突的腹侧导向在[具体生物名称未给出]和[具体生物名称未给出]中同样严重。总之，这些结果表明[具体生物名称未给出]保留了短程功能但缺乏长程功能。最后，来自非腹侧来源的异位[具体生物名称未给出]表达可以挽救[具体生物名称未给出]和[具体生物名称未给出]中的背侧和腹侧导向缺陷。因此，背腹轴突导向不需要UNC-6的腹侧定向来源，并且UNC-6可以作为背腹轴突导向的允许性而非指导性线索。可能，UNC-6是激活细胞内在极性的允许性信号；或者UNC-6与另一种以定向方式起作用的信号共同发挥作用。在任何一种情况下，UNC-6的作用都是使UNC-40/DCC的促突出活性在生长方向上极化。
