Lypd6, a member of the Ly-6/uPAR family, is a GPI-tethered protein expressed in the brain. It has two main functions: enhancing Wnt/β-catenin signaling by promoting Lrp6 phosphorylation in raft plasma membrane domains [2,3], and acting as a negative modulator of the cholinergic system in the brain, interacting with nicotinic acetylcholine receptors (nAChRs) [1]. Lypd6 is crucial in embryogenesis, tissue homeostasis, and in the regulation of neural functions. Genetic models, such as knockout mice, have been instrumental in studying its functions.

In Lypd6 knockout (KO) mice, loss of Lypd6 leads to decreased anxiety-like behavior as seen in reduced digging in the marble burying test and increased time in the open area of the elevated zero maze test. Additionally, acute nicotine administration accentuates the genotype difference in digging behavior between KO and wild-type mice. Electrophysiology in dorsal raphe nuclei neurons from KO mice shows enhanced nicotine-evoked whole-cell currents, indicating Lypd6's role in modulating cholinergic responses related to anxiety [5]. Overexpression of Lypd6 in a mouse model via intracerebroventricular delivery causes memory impairment, acute stress, downregulation of hippocampal and amygdala dendritic spine density, and depression of the cholinergic system, suggesting its link to cognitive decline and anxiety-related disorders [4].

In conclusion, Lypd6 plays essential roles in the Wnt/β-catenin and cholinergic systems. Mouse models, especially KO models, have revealed its significance in anxiety-related behaviors and cognitive functions. The findings suggest that Lypd6 may be a potential target for treating neuropsychiatric disorders associated with cholinergic system dysregulation, such as anxiety and cognitive decline [4,5].

References:

1. Kulbatskii, Dmitrii, Shenkarev, Zakhar, Bychkov, Maxim, Kirpichnikov, Mikhail, Lyukmanova, Ekaterina. 2021. Human Three-Finger Protein Lypd6 Is a Negative Modulator of the Cholinergic System in the Brain. In Frontiers in cell and developmental biology, 9, 662227. doi:10.3389/fcell.2021.662227. https://pubmed.ncbi.nlm.nih.gov/34631692/

2. Özhan, Günes, Sezgin, Erdinc, Wehner, Daniel, Schwille, Petra, Weidinger, Gilbert. . Lypd6 enhances Wnt/β-catenin signaling by promoting Lrp6 phosphorylation in raft plasma membrane domains. In Developmental cell, 26, 331-45. doi:10.1016/j.devcel.2013.07.020. https://pubmed.ncbi.nlm.nih.gov/23987510/

3. Zhao, Yuguang, Ren, Jingshan, Lu, Weixian, Harlos, Karl, Jones, Edith Yvonne. 2018. Structure of the Wnt signaling enhancer LYPD6 and its interactions with the Wnt coreceptor LRP6. In FEBS letters, 592, 3152-3162. doi:10.1002/1873-3468.13212. https://pubmed.ncbi.nlm.nih.gov/30069874/

4. Isaev, Aizek B, Bychkov, Maxim L, Kulbatskii, Dmitrii S, Kirpichnikov, Mikhail P, Lyukmanova, Ekaterina N. 2024. Upregulation of cholinergic modulators Lypd6 and Lypd6b associated with autism drives anxiety and cognitive decline. In Cell death discovery, 10, 444. doi:10.1038/s41420-024-02211-z. https://pubmed.ncbi.nlm.nih.gov/39433742/

5. Arvaniti, Maria, Polli, Filip S, Kohlmeier, Kristi A, Thomsen, Morten S, Andreasen, Jesper T. 2017. Loss of Lypd6 leads to reduced anxiety-like behaviour and enhanced responses to nicotine. In Progress in neuro-psychopharmacology & biological psychiatry, 82, 86-94. doi:10.1016/j.pnpbp.2017.11.025. https://pubmed.ncbi.nlm.nih.gov/29195920/