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Exp Neurobiol 2020; 29(1): 1-10
Published online February 29, 2020
© The Korean Society for Brain and Neural Sciences
Kyungchul Noh1, Jung-Cheol Park2, Jung-Soo Han2 and Sung Joong Lee1*
1Department of Physiology and Neuroscience, Dental Research Institute, Seoul National University School of Dentistry, Seoul 08826, 2Department of Biological Science, Konkuk University, Seoul 05029, Korea
Correspondence to: *To whom correspondence should be addressed.
TEL: 82-2-880-2309, FAX: 82-2-880-2309
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License
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Cell-to-cell adhesion is important for maintenance of brain structure and function. Abnormal neuronal cell adhesion and loss of its connectivity are considered a main cause of psychiatric disorders such as major depressive disorder (MDD). Various cell adhesion molecules (CAMs) are involved in neuronal cell adhesions and thereby affect brain functions such as learning and memory, cognitive functions, and psychiatric functions. Compared with other CAMs, neuronal growth regulator 1 (Negr1) has a distinct functioning mechanism in terms of its cross-talk with cytokine receptor signaling. Negr1 is a member of the immunoglobulin LON (IgLON) family of proteins and is involved in neuronal outgrowth, dendritic arborization, and synapse formation. In humans, Negr1 is a risk gene for obesity based on a genome-wide association study. More recently, accumulating evidence supports that it also plays a critical role in psychiatric disorders. In this review, we discuss the recent findings on the role of Negr1 in MDD, focusing on its regulatory mechanism. We also provide evidence of putative involvement of Negr1 in other psychiatric disorders based on the novel behavioral phenotypes of Negr1 knockout mice.
Keywords: Cell adhesion molecule (CAM), Neuronal growth regulator 1 (Negr1), Immunoglobulin LON family (IgLON), Psychiatric disorders, Major depressive disorder (MDD)
Tight connections between presynaptic bouton and postsynaptic density by cell adhesion molecules (CAMs) are critical to form stable and functional synapses [1–6]. Two types of CAMs, Ca2+-dependent and Ca2+-independent, work as synaptic adhesion molecules in the central nervous system (CNS). Cadherin and selectin are dependent on Ca2+ ion for binding, while members of the immunoglobulin superfamily (IgSF) contribute to establishment and remodeling of neuronal synapses [7–9] in a Ca2+-independent manner. Among IgSF, immunoglobulin LON (IgLON) family proteins function as synaptic adhesion molecules that play important roles in axonal extension, dendritic arborization, and synaptogenesis during brain development [10–13]. Molecules of the IgLON family including LAMP, OBCAM, neurotrimin, GP55, and AvGP50 have three Ig-like domains and localize to the membrane raft of the Triton-insoluble low-density fraction via a glycosylphosphatidylinositol (GPI)-anchor [14–18]. Among the IgLONs, neuronal growth regulator 1 (Negr1), also named Kilon (a kindred of IgLON), is the most recently characterized IgLON subgroup member [19, 20].
Negr1 is a GPI-anchored membrane protein of 46 kDa with three immunoglobulin-like domains and six putative glycosylation sites (Fig. 1A) [19, 20]. Initial studies during mouse development show that Negr1 expression gradually increases during post-natal brain development and reaches a constant level in adulthood [20–22]. Both immunohistochemistry and western blot analysis confirm that the Negr1 protein is expressed in the cerebral cortex and hippocampus of the adult rat .
The role of Negr1 in synaptogenesis and neurite outgrowth has been reported mainly in
Since the cloning of negr1, the function of this putative synaptic adhesion molecule has been investigated mainly in synaptogenesis and neurite outgrowth. Therefore, it was unexpected when human genetics studies showed Negr1 as a major risk factor for human obesity by genome-wide association studies (GWAS) [28–31]. These studies have been replicated in human subjects of various ethnic groups including Europeans [32–37], Asians [38–40], and African Americans [41, 42], suggesting that common genetic variants of
Currently, the molecular mechanisms regarding how Negr1 serve as a risk factor for human obesity are not clear. Although an
Dennis et al.  recently reported that Negr1 has effects on brain structure independent of its effects on obesity. By comparing white matter integrity and SNPs of Negr1 in healthy young adults, they concluded that
Maccarrone et. al.  screened for a disease-specific protein bio-signature in the cerebrospinal fluid (CSF) of MDD patients and found a significant elevation of Negr1 in these patients compared to healthy individuals. The involvement of Negr1 in MDD was also supported by a study screening for putative genetic traits associated with treatment response of selective serotonin reuptake inhibitors (SSRIs)  in MDD patients. In this recent cross-trait meta-analysis study,
To understand the relationship between Negr1 and psychiatric disorders, we used
In addition to MDD, Negr1 has been implicated in other psychiatric disorders and neurological diseases. Several studies have provided evidence that Negr1 is involved in Alzheimer disease (AD) [69, 70], autism spectrum disorder (ASD) , and schizophrenia (SCZ) . A GWAS study using patients with comorbid MDD and AD identified
To address the breadth of Negr1 influence in psychiatric disorders, we subjected our
In this short review, we summarized and discussed recent studies on the role of Negr1 in psychiatric disorders. Accumulating evidence based on both human and animal studies support critical roles of Negr1 in psychiatric disorders such as MDD, schizophrenia, and ASD. However, the molecular and cellular mechanisms underlying Negr1’s role in these psychiatric disorders remain elusive. Considering the diverse brain expression pattern of Negr1 including hippocampus, sensory cortex, and prefrontal cortex region, future studies using brain region/cell type-specific negr1 conditional knockout mice will be instrumental to elucidate the pathophyisological mechanisms of Negr1 in psychiatric disorders. Concerted effort in the fields of genetics, molecular biology, neuroscience, and clinical psychiatric medicine are also needed in the future to dissect the exact pathophysiologic function of this molecule. Although the mechanisms need to be elucidated, studies have proposed Negr1 as a novel target for treatment of psychiatric disorders. Considering the high comorbidity between depression and obesity, Negr1 may act as a central hub bridging the two diseases. If so, Negr1 can be a critical common target for treatment of individuals with MDD comorbid with obesity.
This work was supported by the Samsung Science & Technology Foundation (SSTF-BA1502-13).
(A) Structure of Negr1. Loops represent immunoglobulin-like domains. Lines ending with dots are putative
Spatial memory impairments of
Performances of the
Studies showing putative involvement of Negr1 in psychiatric disorders
|Literature||Disease targeted||Subject||Main findings|
|Singh et al. 2019 ||General psychiatric disorders|
- Enlarged ventricle.
- Decreased number of parvalbumin-positive inhibitory interneurons in hippocampus.
- Hyperactivity in social interaction.
- Impaired social dominance behavior.
|Maccarrone et al. 2013 ||Major depressive disorder (MDD), Bipolar disorder, Schizophrenia (SCZ)||Human|
- Identification of association of Negr1 as a MDD-specific protein biosignature in cerebrospinal fluid of MDD patient.
|Szczurkowska et al. 2018 ||Autism spectrum disorder (ASD)|
- Impaired ultrasonic vocalization.
- Increased latency to respond to thermal stimuli.
- Less sniffing, More grooming.
|Ni et al. 2018 ||Major depressive disorder (MDD), Alzheimer’s disease (AD)||Human, mouse|
- Identification of Negr1 as a common variants in the MDD GWAS loci with AD.
- Reduced mRNA expression in the entorhinal cortex and temporal cortex in human AD patient.
- Significant correlation of Negr1 mRNA expression level with both amyloid-β (Aβ) and tau (Tau) burden in AD mouse model.
|Karis et al. 2018 ||Schizophrenia (SCZ)||Human|
- Increased Negr1 transcript level in dorsolateral prefrontal cortex in SCZ patient.
|Noh et al. 2019 ||Major depressive disorder (MDD)|
- Increased anxiety- and depressive-like behavior.
- Decreased hippocampal neurogenesis.
- Reduced Lipocalin-2 (Lcn2) expression in hippocampus.
- Impaired LTP and mEPSC in hippocampal dentate gyrus.
|Amare et al. 2018 ||Major depressive disorder (MDD)||Human|
- Identification of association of Negr1 in SSRI treatment response.
Cognitive phenotypes of
|Types of memory||Cognitive tasks||Results||Involved brain regions|
|Spatial memory||Morris water maze||+||Hippocampus|
|Recognition memory||Novel object recognition||n.s.||Hippocampus, Cerebral cortex|
|Novel location recognition||n.s.|
|Fear memory||Contextual fear conditioning||n.s.||Cerebral cortex, Amygdala|
+, significant behavior; n.s., not significant.