From Bound Cells Comes a Sound Mind: The Role of Neuronal Growth Regulator 1 in Psychiatric Disorders

Abstract

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.

Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model

“…This cluster was unique because many top upregulated genes are associated with neural development or nerve regeneration. These genes included NEGR1, MYOC, EPHA3, COL15A1, PTN, FBLN5, PDGFRβ , and THY-1 ( Figure 7E , Supplementary Table 3 ) ( 72 , 94 , 100 – 105 ). In addition to these genes, this cluster was enriched for both “Cell-Matrix Adhesion” and “Regulation of Cell Junction Assembly” ( Figure 7F ).…”

“…Specifically, EPHA3 and NEGR1 are primarily expressed in the adult brain and promote neuronal synaptogenesis and neurite outgrowth ( 106 , 107 ). Loss of NEGR1 in development is associated with decreased numbers of synapses and dendritic length, resulting in anxiety and depression-like behaviors in mice ( 100 ). Furthermore, FBLN5 and PDGFRβ are found to be upregulated immediately following sciatic nerve crushing in rats.…”

The Risk Genes for Neuropsychiatric Disorders negr1 and opcml Are Expressed throughout Zebrafish Brain Development

“…NEGR1 −/− mice exhibit a reduced volume of brain regions, including the hippocampus. Specifically, the parvalbumin-positive interneurons were significantly reduced [ 34 , 38 ]. In OPCML-deficient mice, the hippocampal area develops largely normally, but alterations in hippocampus-dependent spatial learning and memory were observed [ 52 ].…”

“…These findings suggest a role of NEGR1 and OPCML in partially overlapping brain areas. In vitro studies and loss-of-function investigations in mammalian animal systems have started to shed light on the mechanisms causing the human phenotypes [ 22 , 33 , 34 , 35 ]. However, much of the cellular and molecular basis underlying the genes’ role in these disorders in vivo has remained elusive.…”

Molecular pathways of major depressive disorder converge on the synapse

“…Top MDD-associated genes in the latest GWAS study are linked to synaptic function: the neuronal growth regulator 1 ( NEGR1 ) controls synapse number and dendritic maturation [ 19 ]. NEGR1 SNPs have also been associated with low white matter integrity [ 20 ] and responsiveness to selective serotonin (5-HT) reuptake inhibitors [ 21 ].…”