Does Lrig1 expression have a relationship with ERBB1 and ERBB2 expression in schizophrenia?

Year 2025, Volume: 50 Issue: 1, 221 - 230, 31.03.2025

Sevgi Karabulut Uzunçakmak , Halil Özcan , Pelin Aydın , Zekai Halıcı

https://doi.org/10.17826/cumj.1624159

Abstract

Purpose: This study aims to investigate Lrig1 expression and to reveal the possible relationship between Lrig1, ERBB1 and ERBB2 in schizophrenia.
Materials and Methods: In this study, peripheral blood samples of 70 schizophrenia patients and 60 healthy controls were used. Real Time PCR was applied for Lrig1, ERBB1 and ERBB2 gene expression analysis.
Results: The level of Lrig1 mRNA was lower in the patients when compared to healthy controls. Expression levels of ERBB1 and ERBB2 were decreased in the patients versus in the healthy controls. According to the receiver operating characteristic curve analysis, the three genes had the power to discriminate the patients from the healthy controls (Lrig1 AUC: 0.66, ERBB1 AUC: 0.64, ERBB2 AUC: 0.79). There was a weak, positive correlation between the Lrig1 and ERBB1 expressions in the schizophrenia patients. No significant correlation was detected between the Lrig1 and ERBB2 expressions or the ERBB1 and ERBB2 expressions in the patients.
Conclusion: The results revealed that the Lrig1 and ERBB relationship changes in schizophrenia. These genes may have the potential to be a biomarker that can be used in schizophrenia.

Keywords

Schizophrenia, Lrig1, ERBB1, ERBB2, EGFR

Ethical Statement

The study was conducted at the Atatürk University Psychiatry Department after receiving approval from the Atatürk University Non-Interventional Clinical Research Ethics Committee (Decision no;3-39).

Supporting Institution

No

Project Number

No project

Thanks

NO

Lrig1 ekspresyonunun şizofrenide ERBB1 ve ERBB2 ekspresyonuyla ilişkisi var mıdır?

Abstract

Amaç: Bu çalışmanın amacı şizofrenide Lrig1 ekspresyonunu araştırmak ve şizofrenide Lrig1, ERBB1 ve ERBB2 arasındaki olası ilişkiyi ortaya koymaktır.
Gereç ve Yöntem: Çalışmaya 70 şizofreni hastası ve 60 sağlıklı bireye ait periferik kan örneği dahil edildi. Lrig1, ERBB1 ve ERBB2 gen ekspresyon analizi için Real Time PCR kullanıldı.
Bulgular: Lrig1 mRNA düzeyi hastalarda sağlıklı kontrollere nispeten düşüktü. ERBB1 ve ERBB2'nin hastalarda sağlıklı kontrollerden daha düşük ifade düzeylerine sahip olduğu görüldü. Alıcı işletim karakteristiği eğrisi analizine göre, üç genin hastaları sağlıklı kontrollerden ayırt etme gücü vardı (Lrig1 AUC: 0,66, p = 0,006, ERBB1 AUC: 0,64 ERBB2 AUC: 0,79). Şizofreni hastalarında Lrig1 ve ERBB1 ifadeleri arasında zayıf, pozitif bir korelasyon vardı. Hastaların gen ifadelerine bakıldığında Lrig1 ile ERBB2 arasında ve ERBB1 ile ERBB2 arasında anlamlı bir korelasyon olmadığı görülmüştür.
Sonuç: Sonuçlar Lrig1 ve ERBB ilişkisinin şizofrenide değiştiğini ortaya koydu. Bu genlerin şizofrenide kullanılabilecek bir biyobelirteç olma potansiyeline sahip olduğu düşünülmektedir.

Keywords

Şizofreni, Lrig1, ERBB1, ERBB2, EGFR

Project Number

No project

References

• Correll CU, Detraux J, De Lepeleire J, De Hert M. Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder. World Psychiatry. 2015;14:119-36.
• Gogtay N, Vyas NS, Testa R, Wood SJ, Pantelis C. Age of onset of schizophrenia: perspectives from structural neuroimaging studies. Schizophr Bull. 2011;37:504-13.
• Laederich MB, Funes-Duran M, Yen L, Ingalla E, Wu X, Carraway K et al. The Leucine-rich repeat protein LRIG1 Is a negative regulator of ERBB family receptor tyrosine Kinases. J Biol Chem. 2004;279:47050-6.
• Alsina FC, Hita FJ, Fontanet PA, Irala D, Hedman H, Ledda F et al. Lrig1 is a cell‐intrinsic modulator of hippocampal dendrite complexity and <scp>BDNF</scp> signaling. EMBO Rep. 2016;17:601-6.
• Karabulut Uzunçakmak S, Şahin A, Tavaci Özçelik A, Halici Z. LRIG1 levels in chronic rhinosinusitis with nasal polyps. Cukurova Med J. 2023;48:323-9.
• Ji Y, Kumar R, Gokhale A, Chao H, Rycaj K, Chen X et al. LRIG1, a regulator of stem cell quiescence and a pleiotropic feedback tumor suppressor. Semin Cancer Biol. 2022;82:120-33.
• Gur G, Rubin C, Katz M, Amit I, Citri A, Nilsson J et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. EMBO J. 2004;23:3270-81.
• Hita FJ, Bekinschtein P, Ledda F, Paratcha G. Leucine‐rich repeats and immunoglobulin‐like domains 1 deficiency affects hippocampal dendrite complexity and impairs cognitive function. Dev Neurobiol. 2021;81:774-85.
• Abe Y, Namba H, Zheng Y, Nawa H. In situ hybridization reveals developmental regulation of ERBB1-4 mRNA expression in mouse midbrain: implication of ERBB receptors for dopaminergic neurons. Neuroscience. 2009;161:95-110.
• Iwakura Y, Nawa H. ERBB1-4-dependent EGF/neuregulin signals and their cross talk in the central nervous system: pathological implications in schizophrenia and parkinson’s disease. Front Cell Neurosci. 2013;7:4.
• Karati D, Kumar D. Tyrosine kinase as therapeutic target of neurodegenerative disorders. Brain Disord. 2025;17:100193.
• Ibanez CF. Structure and physiology of the RET receptor tyrosine kinase. Cold Spring Harb Perspect Biol. 2013;5:a009134.
• Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer. 2001;8:11-31.
• Aguirre A, Rizvi TA, Ratner N, Gallo V. Overexpression of the epidermal growth factor receptor confers migratory properties to nonmigratory postnatal neural progenitors. J Neurosci. 2005;25:11092-106.
• Iwakura Y, Zheng Y, Sibilia M, Abe Y, Piao Y, Yokomaku D et al. Qualitative and quantitative re‐evaluation of epidermal growth factor‐ERBB1 action on developing midbrain dopaminergic neurons in vivo and in vitro : target‐derived neurotrophic signaling (Part 1). J Neurochem. 2011;118:45-56.
• Seshadri S, Kamiya A, Yokota Y, Prikulis I, Kano S, Takagi A et al. Disrupted-in-schizophrenia-1 expression is regulated by β-site amyloid precursor protein cleaving enzyme-1–neuregulin cascade. Proc Natl Acad Sci. 2010;107:5622-7.
• Malberg JE. Implications of adult hippocampal neurogenesis in antidepressant action. J Psychiatry Neurosci. 2004;29:196-205.
• Erdfelder E, Faul F, Buchner A. GPOWER: A general power analysis program. Behav Res Methods Instrum Comput. 1996;28:1-11.
• American Psychiatric Association. Diagnostic and Statistical Manual Of Mental Disorders 5th Edition (DSM-5). Washington DC, American Psychiatric Association, 2013
• World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191-4.
• Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for Schizophrenia. Schizophr Bull. 1987;13:261-76.
• Guy W. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD, US Department of Heath, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration, 1976.
• Endicott J. The Global assessment scale. Arch Gen Psychiatry. 1976;33:766.
• Overall JE, Gorham DR. The brief psychiatric rating scale. Psychol Rep. 1962;10:799-812.
• Meijer BJ, Smit WL, Koelink PJ, Westendorp B, Boer R, Mer J et al. Endoplasmic reticulum stress regulates the intestinal stem cell state through CtBP2. Sci Rep. 2021;11:9892.
• Weng X, Zhang H, Ye J, Kan M, Liu F, Wang T et al. Hypermethylated epidermal growth factor receptor (EGFR) promoter is associated with gastric cancer. Sci Rep. 2015;5:10154.
• Ikink GJ, Boer M, Bakker ERM, Hilkens J. IRS4 induces mammary tumorigenesis and confers resistance to HER2-targeted therapy through constitutive PI3K/AKT-pathway hyperactivation. Nat Commun. 2016;7:13567.
• Jan YN, Jan LY. Branching out: mechanisms of dendritic arborization. Nat Rev Neurosci. 2010;11:316-28.
• Takashima N, Odaka YS, Sakoori K, Akagi T, Hashikawa T, Morimura N et al. Impaired cognitive function and altered hippocampal synapse morphology in mice lacking Lrrtm1, a gene associated with schizophrenia. Tang YP, ed. PLoS One. 2011;6:e22716.
• De Vincenti AP, Bonafina A, Ledda F, Paratcha G. Lrig1 regulates cell fate specification of glutamatergic neurons via FGF-driven JAK2/STAT3 signaling in cortical progenitors. Development. 2024;151:dev202879.
• Penzes P, Woolfrey KM, Srivastava DP. Epac2-mediated dendritic spine remodeling: Implications for disease. Mol Cell Neurosci. 2011;46:368-80.
• Morimura N, Yasuda H, Yamaguchi K, Katayama K, Hatayama M, Tomioka N et al. Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice. Nat Commun. 2017;8:15800.
• Shmelkov S V, Hormigo A, Jing D, Proenca C, Bath K, Milde T, et al. Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive–like behaviors in mice. Nat Med. 2010;16:598-602.
• Nilsson J, Vallbo C, Guo D, Golovleva I, Hallberg B, Henriksson R et al. Cloning, characterization, and expression of human LIG1. Biochem Biophys Res Commun. 2001;284:1155-61.
• Sasabayashi D, Yoshimura R, Takahashi T, Takayanagi Y, Hishiyama S, Higuchi Y et al. Reduced hippocampal subfield volume in schizophrenia and clinical high-risk state for psychosis. Front Psychiatry. 2021;12:642048.
• Ouzikov S, Edwards KM, Anandampillai T, Watanabe S, Cassasbuenas D, Siu K et al. LRIG1 controls proliferation of adult neural stem cells by facilitating TGFβ and BMP signalling pathways. Commun Biol. 2024;7:845.
• Cavaleri D, Moretti F, Bartoccetti A, Mauro S, Crocamo C, Carra G et al. The role of BDNF in major depressive disorder, related clinical features, and antidepressant treatment: Insight from meta-analyses. Neurosci Biobehav Rev. 2023;149:105159.
• Futamura T, Toyooka K, Iritani S, Niizato K, Nakamura R, Tsuchiya K et al. Abnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients. Mol Psychiatry. 2002;7:673-82.
• Aguirre A, Rubio ME, Gallo V. Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature. 2010;467:323-7.
• Walker RA. The ERBB/HER type 1 tyrosine kinase receptor family. J Pathol. 1998;185:234-5.
• Mostaid MS, Lee TT, Chana G, Sundram S, Weickert C, Pantelis C et al. Peripheral transcription of NRG-ERBB pathway genes are upregulated in treatment-resistant schizophrenia. Front Psychiatry. 2017;8:225.
• Kéri S, Szabó C, Kelemen O. Uniting the neurodevelopmental and immunological hypotheses: Neuregulin 1 receptor ERBB and Toll-like receptor activation in first-episode schizophrenia. Sci Rep. 2017;7:4147.
• Jeong D, Lozano Casasbuenas D, Gengatharan A, Edwards K, Saghatelyan A, Kaplan D et al. LRIG1-mediated inhibition of egf receptor signaling regulates neural precursor cell proliferation in the neocortex. Cell Rep. 2020;33:108257.
• Jiang X, Li H. Overexpression of LRIG1 regulates PTEN via MAPK/MEK signaling pathway in esophageal squamous cell carcinoma. Exp Ther Med. 2016;12:2045-52.
• Herdenberg C, Mutie PM, Billing O, Abdullah A, Strawbridge R, Dahlman I et al. LRIG proteins regulate lipid metabolism via BMP signaling and affect the risk of type 2 diabetes. Commun Biol. 2021;4:90.