SLIT2 repellent is cleaved by TLL1 protease and promotes sensory axon fasciculation.

IF 3.6 2区生物学 Q1 DEVELOPMENTAL BIOLOGY

Development Pub Date : 2026-08-15 Epub Date: 2026-03-26 DOI:10.1242/dev.205124

Lauren E Jones, Riley Kellermeyer, Ria Anand, Jayden Watson, Leigh Smith, Xieyi Huang, Zhuqing Wang, Wei Yan, Hua Zhang, Cynthia C Mastick, Thomas Kidd, Grant S Mastick

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引用次数: 0

Abstract

SLIT2 is a secreted protein that repels axons from the CNS midline. Full-length SLIT2 (SLIT2-FL) is proteolytically cleaved into two fragments, SLIT2-N and SLIT2-C. SLIT2-FL and SLIT2-N have opposing biological effects on cultured dorsal root ganglion (DRG) axons. This study identified SLIT2 cleavage mechanisms and functional significance for DRG axon guidance. The Tolloid-related protease TLL1 cleaved SLIT2 in cultured cells, with TLL1 requiring activation by furin/prohormone convertases. We used CRISPR editing in mice to produce a Slit2ΔTLS allele lacking the TLL1 cleavage site. Slit2ΔTLS embryos retained dorsal repulsion of DRG axons, in contrast to DRG midline invasion in Slit2 knockouts. However, DRG axons in Slit2 knockouts and Slit2ΔTLS mutants showed reduced fasciculation of rootlets and longitudinal DRG projections. In vitro, SLIT2-N promoted fasciculation of DRG axons. These results suggest that proteolytic cleavage generates additional SLIT2 biological functions for organizing DRG central axon projections.

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SLIT2驱蚊剂被TLL1蛋白酶裂解，促进感觉轴突的束控。

SLIT2是一种分泌蛋白，它排斥中枢神经系统中线的轴突。全长SLIT2 （SLIT2- fl）被蛋白水解成两个片段，SLIT2- n和SLIT2- c。SLIT2-FL和SLIT2-N对培养的背根神经节（DRG）轴突具有相反的生物学作用。本研究明确了SLIT2切割机制及其在DRG轴突引导中的功能意义。Tolloid相关蛋白酶TLL1在培养细胞中切割SLIT2， TLL1需要furin/原激素转化酶激活。我们在小鼠中使用CRISPR编辑技术产生了一个缺少TLL1切割位点的Slit2DTLS等位基因。Slit2DTLS胚胎保留了DRG轴突的背斥力，与Slit2基因敲除时DRG中线侵袭形成对比。然而，在Slit2敲除和Slit2DTLS突变体中，DRG轴突显示出根的束状化和纵向DRG突起的减少。在体外，SLIT2-N促进DRG轴突的束状化。这些结果表明，蛋白水解裂解在组织DRG中央轴突突起方面产生了额外的SLIT2生物学功能。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Development 生物-发育生物学

CiteScore

6.70

自引率

4.30%

发文量

433

审稿时长

3 months

期刊介绍： Development’s scope covers all aspects of plant and animal development, including stem cell biology and regeneration. The single most important criterion for acceptance in Development is scientific excellence. Research papers (articles and reports) should therefore pose and test a significant hypothesis or address a significant question, and should provide novel perspectives that advance our understanding of development. We also encourage submission of papers that use computational methods or mathematical models to obtain significant new insights into developmental biology topics. Manuscripts that are descriptive in nature will be considered only when they lay important groundwork for a field and/or provide novel resources for understanding developmental processes of broad interest to the community. Development includes a Techniques and Resources section for the publication of new methods, datasets, and other types of resources. Papers describing new techniques should include a proof-of-principle demonstration that the technique is valuable to the developmental biology community; they need not include in-depth follow-up analysis. The technique must be described in sufficient detail to be easily replicated by other investigators. Development will also consider protocol-type papers of exceptional interest to the community. We welcome submission of Resource papers, for example those reporting new databases, systems-level datasets, or genetic resources of major value to the developmental biology community. For all papers, the data or resource described must be made available to the community with minimal restrictions upon publication. To aid navigability, Development has dedicated sections of the journal to stem cells & regeneration and to human development. The criteria for acceptance into these sections is identical to those outlined above. Authors and editors are encouraged to nominate appropriate manuscripts for inclusion in one of these sections.