Cd99l2 regulates excitatory synapse development and restrains immediate-early gene activation

Minji Kang; Sang Ho Yoon; Minkyung Kang; Seung Pyo Park; Woo Seok Song; Jungho Kim; Seungha Lee; Da-Ha Park; Jae-Man Song; Beomsue Kim; Kyung Hee Park; Eun-Hye Joe; Hyun Goo Woo; Seong Hoe Park; Bong-Kiun Kaang; Dohyun Han; Yong-Seok Lee; Myoung-Hwan Kim; Young Ho Suh

doi:10.1016/j.celrep.2024.115155

Cd99l2 regulates excitatory synapse development and restrains immediate-early gene activation

Cell Rep. 2025 Jan 13;44(1):115155. doi: 10.1016/j.celrep.2024.115155. Online ahead of print.

Authors

Minji Kang¹, Sang Ho Yoon², Minkyung Kang², Seung Pyo Park¹, Woo Seok Song², Jungho Kim¹, Seungha Lee¹, Da-Ha Park¹, Jae-Man Song¹, Beomsue Kim³, Kyung Hee Park⁴, Eun-Hye Joe⁴, Hyun Goo Woo⁵, Seong Hoe Park⁶, Bong-Kiun Kaang⁷, Dohyun Han⁸, Yong-Seok Lee⁹, Myoung-Hwan Kim¹⁰, Young Ho Suh¹¹

Affiliations

¹ Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea; Neuroscience Research Institute, Medical Research Center, Seoul National University, Seoul 03080, South Korea; Transplantation Research Institute, Medical Research Center, Seoul National University, Seoul 03080, South Korea.
² Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea; Neuroscience Research Institute, Medical Research Center, Seoul National University, Seoul 03080, South Korea; Department of Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea.
³ Neural Circuits Research Group, Korea Brain Research Institute, Daegu 41062, South Korea.
⁴ Department of Pharmacology, Ajou University School of Medicine, Suwon 16499, South Korea.
⁵ Department of Physiology, Ajou University School of Medicine, Suwon 16499, South Korea.
⁶ Transplantation Research Institute, Medical Research Center, Seoul National University, Seoul 03080, South Korea; Department of Medicine, Seoul National University College of Medicine, Seoul 03080, South Korea.
⁷ Center for Cognition and Sociality, Life Science Institute, Institute for Basic Science (IBS), Daejeon 34126, South Korea.
⁸ Department of Medicine, Seoul National University College of Medicine, Seoul 03080, South Korea; Department of Transdisciplinary Medicine, Seoul National University Hospital, Seoul 03080, South Korea. Electronic address: [email protected].
⁹ Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea; Neuroscience Research Institute, Medical Research Center, Seoul National University, Seoul 03080, South Korea; Department of Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea; Wide River Institute of Immunology, Seoul National University, Hongcheon 25159, South Korea. Electronic address: [email protected].
¹⁰ Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea; Neuroscience Research Institute, Medical Research Center, Seoul National University, Seoul 03080, South Korea; Department of Physiology, Seoul National University College of Medicine, Seoul 03080, South Korea; Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, South Korea. Electronic address: [email protected].
¹¹ Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, South Korea; Neuroscience Research Institute, Medical Research Center, Seoul National University, Seoul 03080, South Korea; Transplantation Research Institute, Medical Research Center, Seoul National University, Seoul 03080, South Korea. Electronic address: [email protected].

PMID: 39808524
DOI: 10.1016/j.celrep.2024.115155

Abstract

Cd99 molecule-like 2 (Cd99l2) is a type I transmembrane protein that plays a role in the transmigration of leukocytes across vascular endothelial cells. Despite its high expression in the brain, the role of Cd99l2 remains elusive. We find that Cd99l2 is expressed primarily in neurons and positively regulates neurite outgrowth and the development of excitatory synapses. We demonstrate that Cd99l2 inversely regulates the expression of immediate-early genes (IEGs), including Arc, Egr1, and c-Fos, by inhibiting the activity of the transcription factors CREB and SRF. Neuronal inactivation increases the transport of Cd99l2 to the cell surface from recycling endosomes, thereby enhancing Cd99l2-mediated inhibitory signaling. Additionally, Cd99l2 knockout mice exhibit impaired excitatory synaptic transmission and plasticity in the hippocampus, along with deficits in spatial memory and contextual fear conditioning. Based on these findings, we propose that neuronal Cd99l2 functions as a synaptic cell adhesion molecule that inversely controls neuronal activation.

Keywords: CP: Cell biology; CP: Neuroscience; CREB; Cd99l2; SRF; cell adhesion molecule; hippocampus; immediate-early gene; memory; neuronal activity; synapse development; synaptic plasticity.