Site-specific HNK-1 epitope on alternatively spliced fibronectin type-III repeats in tenascin-C promotes neurite outgrowth of hippocampal neurons through contactin-1

Abstract

The human natural killer-1 (HNK-1) carbohydrate epitope, composed of a unique sulfated trisaccharide (HSO3–3GlcAβ1–3Galβ1–4GlcNAc-R), is highly expressed during brain development and regulates higher brain function. However, it remains unclear which glycoprotein carries the HNK-1 epitope in the embryonic brain and the functional role it plays. Here, we showed that one of the major HNK-1 carrier proteins in the embryonic brain is tenascin-C (TNC), an extracellular matrix protein that regulates neurite outgrowth by interacting with the GPI-anchored protein contactin-1 (CNTN). Because the alternatively spliced fibronectin type-III (FNIII) repeats in TNC give rise to many isoforms and affect neuronal function, we evaluated neurite outgrowth of primary hippocampal neurons on purified recombinant FNIII repeats with or without the HNK-1 epitope as a substrate. We found that the presence of the HNK-1 epitope on the C domain of TNC promoted neurite outgrowth, and that this signal was mediated by CNTN, which is an HNK-1-expressing neuronal receptor. The neurite-promoting activity of the HNK-1 epitope on TNC required neuronal HNK-1 expression, which was defective in neurons lacking the glucuronyltransferases GlcAT-P and GlcAT-S. These results suggest that the HNK-1 epitope is a key modifier of TNC and CNTN in the regulation of embryonic brain development.

Pharmacological Modulation of Neurite Outgrowth in Human Neural Progenitor Cells by Inhibiting Non-muscle Myosin II

“…Remodeled ECM at the site of the nervous system injury constitutes a detrimental environment, imposing a major obstacle for axonal regeneration (Beller and Snow, 2014). The effect of these permissive and restrictive ECM components on the neurite outgrowth has been demonstrated in vitro using matured neurons (Ichikawa et al, 2009;Hur et al, 2011;Tan et al, 2011;Nakamura et al, 2019); however, their impact on neural progenitor cells is poorly studied. In the present study, we showed that laminin was essential for maximal neurite growth capacity in human NPCs, and addition of laminin to the inhibitory ECM components weakened their detrimental effect.…”

“…A major determinant of the reduced neuronal regeneration is the diminished axonal growth capacity of mature neurons. Extensive studies have been performed to elucidate the process of axonal growth impairment (Allingham et al, 2005;Medeiros et al, 2006;Tornieri et al, 2006;Rosner et al, 2007;Kubo et al, 2008;Kollins et al, 2009;Hur et al, 2011;Pool et al, 2011;Yu et al, 2012;Roland et al, 2014;Spedden et al, 2014;Xie et al, 2014;Evans et al, 2017;Wang et al, 2017Wang et al, , 2020Tanaka et al, 2018;Basso et al, 2019;Dupraz et al, 2019;, and, in addition to the intrinsic factors, revealed the importance of environmental inhibitory mechanisms in retarded axonal growth (Ichikawa et al, 2009;Hur et al, 2011;Tan et al, 2011;Beller and Snow, 2014;Baldwin and Giger, 2015;Nakamura et al, 2019). Because of the limited availability of human neural tissues, most of these studies used rodent or avian models.…”

Pharmacological Modulation of Neurite Outgrowth in Human Neural Progenitor Cells by Inhibiting Non-Muscle Myosin II

“…Remodeled ECM constitutes a detrimental environment, imposing a major obstacle for axonal regeneration (21). The effect of these permissive and restrictive ECM components on the neurite outgrowth has been demonstrated in vitro using matured neurons (2,(22)(23)(24); however, their impact on neural progenitor cells is poorly studied. In the present study, we investigated the neurite outgrowth of human NPCs on various permissive and restrictive ECMs.…”

“…A major determinant of the hindered neuronal regeneration is the diminished axonal growth capacity of mature neurons. Extensive studies have been performed to elucidate the process of axonal growth impairment (1-19), and revealed the importance of environmental inhibitory mechanisms in addition to the intrinsic factors of retarded axonal growth (2,(20)(21)(22)(23)(24). Because of the limited availability of human neural tissues, most of these studies used rodent or avian models.…”

Re-Expression of Poly/Oligo-Sialylated Adhesion Molecules on the Surface of Tumor Cells Disrupts Their Interaction with Immune-Effector Cells and Contributes to Pathophysiological Immune Escape

“…Interactions of the HNK-1 epitope with chondroitin sulfate proteoglycans enhance neuronal cell adhesion and neurite outgrowth [287]. The HNK-1 epitope (also referred to as L2 or CD57) [289] is also found in a number of other neural cell adhesion molecules, including L1 [290], close homolog of L1 (CHL1) [291,292] myelin-associated glycoprotein (MAG) [110,290,293], melanoma cell adhesion molecule (MCAM) [293], and contactin [153,294].…”