Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA.
Curr Biol. 2012 Mar 6;22(5):373-82. doi: 10.1016/j.cub.2012.01.040. Epub 2012 Feb 9.
Peripheral axons of somatosensory neurons innervate the skin early in development to detect touch stimuli. Embryological experiments had suggested that the skin produces guidance cues that attract sensory axons, but neither the attractants nor their neuronal receptors had previously been identified.
To investigate peripheral axon navigation to the skin, we combined live imaging of developing zebrafish Rohon-Beard (RB) neurons with molecular loss-of-function manipulations. Simultaneously knocking down two members of the leukocyte antigen-related (LAR) family of receptor tyrosine phosphatases expressed in RB neurons, or inhibiting their function with dominant-negative proteins, misrouted peripheral axons to internal tissues. Time-lapse imaging indicated that peripheral axon guidance, rather than outgrowth or maintenance, was defective in LAR-deficient neurons. Peripheral axons displayed a similar misrouting phenotype in mutants defective in heparan sulfate proteoglycan (HSPG) production and avoided regions in which HSPGs were locally degraded.
HSPGs and LAR family receptors are required for sensory axon guidance to the skin. Together, our results support a model in which peripheral HSPGs are attractive ligands for LAR receptors on RB neurons.
感觉神经元的周围轴突在发育早期支配皮肤，以探测触觉刺激。胚胎学实验表明皮肤产生吸引感觉轴突的导向线索，但此前尚未鉴定出这些趋化物及其神经元受体。
为了研究周围轴突向皮肤的导航，我们将发育中的斑马鱼 Rohon-Beard（RB）神经元的实时成像与分子功能丧失操作结合起来。同时敲除 RB 神经元中表达的白细胞抗原相关（LAR）家族受体酪氨酸磷酸酶的两个成员，或用显性负性蛋白抑制其功能，会使周围轴突错误地伸向内部组织。延时成像表明，LAR 缺陷神经元中的缺陷是周围轴突的引导，而不是生长或维持。在缺乏肝素硫酸蛋白聚糖（HSPG）产生和避免 HSPG 局部降解的突变体中，周围轴突表现出类似的错误布线表型。
HSPG 和 LAR 家族受体对于感觉轴突向皮肤的导向是必需的。综上所述，我们的结果支持这样一种模型，即外周 HSPG 是 RB 神经元上 LAR 受体的有吸引力的配体。
