Boyd Patrick, Campbell Leah J, Hyde David R
Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, and Center for Zebrafish Research, Galvin Life Sciences Building, University of Notre Dame, Notre Dame, IN, United States.
Front Cell Dev Biol. 2023 Feb 10;11:1142586. doi: 10.3389/fcell.2023.1142586. eCollection 2023.
Zebrafish possess the innate ability to fully regenerate any neurons lost following a retinal injury. This response is mediated by Müller glia that reprogram and divide asymmetrically to produce neuronal precursor cells that differentiate into the lost neurons. However, little is understood about the early signals that induce this response. Ciliary neurotrophic factor (CNTF) was previously shown to be both neuroprotective and pro-proliferative within the zebrafish retina, however CNTF is not expressed following injury. Here we demonstrate that alternative ligands of the Ciliary neurotrophic factor receptor (CNTFR), such as Cardiotrophin-like cytokine factor 1 (Clcf1) and Cytokine receptor-like factor 1a (Crlf1a), are expressed within Müller glia of the light-damaged retina. We found that CNTFR, Clcf1, and Crlf1a are required for Müller glia proliferation in the light-damaged retina. Furthermore, intravitreal injection of CLCF1/CRLF1 protected against rod photoreceptor cell death in the light-damaged retina and induced proliferation of rod precursor cells in the undamaged retina, but not Müller glia. While rod precursor cell proliferation was previously shown to be Insulin-like growth factor 1 receptor (IGF-1R)-dependent, co-injection of IGF-1 with CLCF1/CRLF1 failed to induce further proliferation of either Müller glia or rod precursor cells. Together, these findings demonstrate that CNTFR ligands have a neuroprotective effect and are required for induction of Müller glia proliferation in the light-damaged zebrafish retina.
斑马鱼具有天生的能力，能够完全再生视网膜损伤后丧失的任何神经元。这种反应是由穆勒胶质细胞介导的，穆勒胶质细胞会重新编程并进行不对称分裂，以产生分化为丧失神经元的神经前体细胞。然而，对于诱导这种反应的早期信号，人们了解甚少。睫状神经营养因子（CNTF）先前已被证明在斑马鱼视网膜内具有神经保护和促增殖作用，然而损伤后CNTF并不表达。在此我们证明，睫状神经营养因子受体（CNTFR）的替代配体，如心肌营养素样细胞因子因子1（Clcf1）和细胞因子受体样因子1a（Crlf1a），在光损伤视网膜的穆勒胶质细胞内表达。我们发现，在光损伤视网膜中，穆勒胶质细胞增殖需要CNTFR、Clcf1和Crlf1a。此外，玻璃体内注射CLCF1/CRLF1可保护光损伤视网膜中的视杆光感受器细胞免于死亡，并诱导未损伤视网膜中视杆前体细胞的增殖，但对穆勒胶质细胞无效。虽然先前已证明视杆前体细胞增殖依赖胰岛素样生长因子1受体（IGF-1R），但将IGF-1与CLCF1/CRLF1共同注射并不能诱导穆勒胶质细胞或视杆前体细胞进一步增殖。总之，这些发现表明，CNTFR配体具有神经保护作用，并且是光损伤斑马鱼视网膜中诱导穆勒胶质细胞增殖所必需的。
