The Netrin-1/DCC Guidance Cue Pathway as a Molecular Target in Depression: Translational Evidence

doi:10.1016/j.biopsych.2020.04.025

Biological Psychiatry

Volume 88, Issue 8, 15 October 2020, Pages 611-624

https://doi.org/10.1016/j.biopsych.2020.04.025 Get rights and content

Abstract

The Netrin-1/DCC guidance cue pathway plays a critical role in guiding growing axons toward the prefrontal cortex during adolescence and in the maturational organization and adult plasticity of prefrontal cortex connectivity. In this review, we put forward the idea that alterations in prefrontal cortex architecture and function, which are intrinsically linked to the development of major depressive disorder, originate in part from the dysregulation of the Netrin-1/DCC pathway by a mechanism that involves microRNA-218. We discuss evidence derived from mouse models of stress and from human postmortem brain and genome-wide association studies indicating an association between the Netrin-1/DCC pathway and major depressive disorder. We propose a potential role of circulating microRNA-218 as a biomarker of stress vulnerability and major depressive disorder.

Section snippets

The Netrin-1/DCC Signaling Pathway

Netrin-1 is a secreted protein that binds to cell surfaces and the extracellular matrix to direct growth of DCC-expressing axons along an adhesive surface (haptotaxis) (26,27,44). It was described as a guidance cue attracting growing axons toward intended targets, where they can establish synaptic contacts (45), but subsequently was also identified as a repellent cue (46,47). The DCC:UNC5 ratio at the cell surface determines Netrin-1 signaling, leading to the recruitment of downstream proteins

Rodent Models of Stress Susceptibility

Depression is a heterogeneous disorder accompanied by a variety of symptoms, including recurrent episodes of sadness, hopelessness, lack of interest or pleasure (anhedonia), social avoidance, and suicidal ideation, among many others (2). Risk of MDD is mediated by the complex interaction between genetic and environmental factors, with the subjective nature of the depressive symptomatology representing a significant challenge for the understanding of its etiology, diagnosis, and treatment (77,78

DCC Receptor Expression in the PFC Is Dysregulated in MDD and Determines Susceptibility to CSDS

To understand the role of the Netrin-1/DCC signaling pathway in depression, we have taken a translational approach using postmortem human brain tissue of adult subjects who were previously diagnosed with MDD and the CSDS mouse model. We measured DCC mRNA expression in the PFC of two separate and independent cohorts of adult subjects with depression who died by suicide and were antidepressant free for at least 3 months before death. Subjects with depression exhibited significantly higher DCC

Genetic Variants in NETRIN-1 and DCC Are Associated With MDD

Twin studies and genome-wide association studies (GWASs) have estimated the heritability of MDD to range between approximately 30% and 40% (77,78). This heritability is thought to be highly complex, with potentially many hundreds of genetic variations being involved, each having miniscule effects. Only a few genetic variants have been identified and consistently replicated in large human cohorts (78). Despite the relatively low heritability of MDD compared with other psychiatric disorders (78,98

Biomarkers of Vulnerability to MDD: Potential Role of miR-218

Biomarkers can provide information about traits that could predict the onset and course of a disease, confirm the clinical status of an individual, and be used to track the effectiveness of a treatment regimen. Biomarkers range from blood pressure to complex biochemical analysis of blood and other peripheral tissues (116,117). Genetic, behavioral, and neuroimaging indices have also been introduced as potential biomarkers of neuropsychiatric disorders (118, 119, 120), but to date there is no

Conclusions and Future Directions

A clear understanding of the pathophysiology of MDD becomes urgently necessary for developing novel preventive strategies and generating evidence-based and rapid-acting therapeutic interventions. This review creates a translational bridge between human and rodent research that points toward Netrin-1 and its DCC receptor as important contributors to the pathophysiology of MDD and opens a new venue for future studies. From the preclinical side, we report studies showing that alterations in DCC

Acknowledgments and Disclosures

This work was supported by the National Institute on Drug Abuse (Grant No. R01DA037911 [to CF]), Canadian Institute for Health Research (Grant No. MOP-74709 [to CF]) and Natural Science and Engineering Research Council of Canada (Grant No. 2982226 [to CF]) and by the National Institute of Mental Health (Grant Nos. P50MH096890 and R01MH051399 [to EJN]) and the Hope for Depression Research Foundation [to EJN]. AT-B received the Integrated Program in Neuroscience fellowship.

We thank Jill Gregory

References (141)

G.S. Malhi et al.
Depression
Lancet
(2018)
H. Akil et al.
Treatment resistant depression: A multi-scale, systems biology approach
Neurosci Biobehav Rev
(2018)
N. Tottenham et al.
Stress and the adolescent brain: Amygdala-prefrontal cortex circuitry and ventral striatum as developmental targets
Neurosci Biobehav Rev
(2016)
K.N. Botteron et al.
Volumetric reduction in left subgenual prefrontal cortex in early onset depression
Biol Psychiatry
(2002)
B.S. McEwen et al.
The brain on stress: Vulnerability and plasticity of the prefrontal cortex over the life course
Neuron
(2013)
V. Lanoue et al.
Branching mechanisms shaping dendrite architecture
Dev Biol
(2019)
E.Y. Van Battum et al.
Axon guidance proteins in neurological disorders
Lancet Neurol
(2015)
L. Finci et al.
Signaling mechanism of the netrin-1 receptor DCC in axon guidance
Prog Biophys Mol Biol
(2015)
R. Meijers et al.
Netrin synergizes signaling and adhesion through DCC
Trends Biochem Sci
(2020)
L.I. Finci et al.
The crystal structure of netrin-1 in complex with DCC reveals the bifunctionality of netrin-1 as a guidance cue
Neuron
(2014)

S.G. Varadarajan et al.

Netrin1 produced by neural progenitors, not floor plate cells, is required for axon guidance in the spinal cord

Neuron

(2017)

K.E. Horn et al.

DCC expression by neurons regulates synaptic plasticity in the adult brain

Cell Rep

(2013)

S.D. Glasgow et al.

Activity-dependent Netrin-1 secretion drives synaptic insertion of GluA1-containing AMPA receptors in the hippocampus

Cell Rep

(2018)

D. Hoops et al.

Making dopamine connections in adolescence

Trends Neurosci

(2017)

Z. Wu et al.

Long-range guidance of spinal commissural axons by Netrin1 and sonic hedgehog from midline floor plate cells

Neuron

(2019)

K. Keino-Masu et al.

Deleted in colorectal cancer (DCC) encodes a netrin receptor

Cell

(1996)

C. Manitt et al.

Where the rubber meets the road: Netrin expression and function in developing and adult nervous systems

Prog Brain Res

(2002)

P.B. Osborne et al.

Localization of immunoreactivity for deleted in colorectal cancer (DCC), the receptor for the guidance factor netrin-1, in ventral tier dopamine projection pathways in adult rodents

Neuroscience

(2005)

S. Reyes et al.

Trophic factors differentiate dopamine neurons vulnerable to Parkinson’s disease

Neurobiol Aging

(2013)

A. Torres-Berrío et al.

DCC confers susceptibility to depression-like behaviors in humans and mice and is regulated by miR-218

Biol Psychiatry

(2017)

X. Wang et al.

The microRNAs let-7 and miR-9 down-regulate the axon-guidance genes Ntn1 and Dcc during peripheral nerve regeneration

J Biol Chem

(2019)

A. Caballero et al.

Mechanisms contributing to prefrontal cortex maturation during adolescence

Neurosci Biobehav Rev

(2016)

B. Larsen et al.

Adolescence as a neurobiological critical period for the development of higher-order cognition

Neurosci Biobehav Rev

(2018)

F.I. Tarazi et al.

Comparative postnatal development of dopamine D₁, D₂ and D₄ receptors in rat forebrain

Int J Dev Neurosci

(2000)

L.M. Reynolds et al.

DCC receptors drive prefrontal cortex maturation by determining dopamine axon targeting in adolescence

Biol Psychiatry

(2018)

D.F. Levinson

The genetics of depression: A review

Biol Psychiatry

(2006)

R.T. Liu et al.

Stress generation in depression: A systematic review of the empirical literature and recommendations for future study

Clin Psychol Rev

(2010)

B. Czéh et al.

Animal models of major depression and their clinical implications

Prog Neuropsychopharmacol Biol Psychiatry

(2016)

P. Willner

The chronic mild stress (CMS) model of depression: History, evaluation and usage

Neurobiol Stress

(2017)

V. Krishnan et al.

Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions

Cell

(2007)

E.L. Newman et al.

Fighting females: Neural and behavioral consequences of social defeat stress in female mice

Biol Psychiatry

(2019)

C.N. Yohn et al.

Social instability is an effective chronic stress paradigm for both male and female mice

Neuropharmacology

(2019)

S.D. Iñiguez et al.

Vicarious social defeat stress induces depression-related outcomes in female mice

Biol Psychiatry

(2018)

J.W. Koo et al.

Role of mesolimbic brain-derived neurotrophic factor in depression

Biol Psychiatry

(2019)

R.C. Kessler et al.

Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication

Arch Gen Psychiatry

(2005)

F. Rice et al.

Characterizing developmental trajectories and the role of neuropsychiatric genetic risk variants in early-onset depression

JAMA Psychiatry

(2019)

T. Paus et al.

Why do many psychiatric disorders emerge during adolescence?

Nat Rev Neurosci

(2008)

R.C. Kessler et al.

Age of onset of mental disorders: A review of recent literature

Curr Opin Psychiatry

(2007)

F.S. Lee et al.

Adolescent mental health—Opportunity and obligation

Science

(2014)

W. Liu et al.

The role of neural plasticity in depression: From hippocampus to prefrontal cortex

Neural Plast

(2017)

Q. Li et al.

Meta-analysis of cortical thickness abnormalities in medication-free patients with major depressive disorder

Neuropsychopharmacology

(2020)

R.S. Duman et al.

Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants

Nat Med

(2016)

H.J. Kang et al.

Decreased expression of synapse-related genes and loss of synapses in major depressive disorder

Nat Med

(2012)

R.S. Duman et al.

Synaptic dysfunction in depression: Potential therapeutic targets

Science

(2012)

E.T. Stoeckli

Understanding axon guidance: Are we nearly there yet?

Development

(2018)

I.V. Beamish et al.

Making connections: Guidance cues and receptors at nonneural cell-cell junctions

Cold Spring Harb Perspect Biol

(2018)

E.W. Dent et al.

The growth cone cytoskeleton in axon outgrowth and guidance

Cold Spring Harb Perspect Biol

(2011)

K. Lai Wing Sun et al.

Netrins: Versatile extracellular cues with diverse functions

Development

(2011)

N.P. Boyer et al.

Revisiting Netrin-1: One who guides (axons)

Front Cell Neurosci

(2018)

C. Dominici et al.

Floor-plate-derived netrin-1 is dispensable for commissural axon guidance

Nature

(2017)

Cited by (32)

Transcriptomic analyses of rats exposed to chronic mild stress: Modulation by chronic treatment with the antipsychotic drug lurasidone
2024, Progress in Neuro-Psychopharmacology and Biological Psychiatry
Exposure to stressful experiences accounts for almost half of the risk for mental disorders. Hence, stress-induced alterations represent a key target for pharmacological interventions aimed at restoring brain function in affected individuals. We have previously demonstrated that lurasidone, a multi-receptor antipsychotic drug approved for the treatment of schizophrenia and bipolar depression, can normalize the functional and molecular impairments induced by stress exposure, representing a valuable tool for the treatment of stress-induced mental illnesses. However, the mechanisms that may contribute to the therapeutic effects of lurasidone are still poorly understood. Here, we performed a transcriptomic analysis on the prefrontal cortex (PFC) of adult male rats exposed to the chronic mild stress (CMS) paradigm and we investigated the impact of chronic lurasidone treatment on such changes. We found that CMS exposure leads to an anhedonic phenotype associated with a down-regulation of different pathways associated to neuronal guidance and synaptic plasticity within the PFC. Interestingly, a significant part of these alterations (around 25%) were counteracted by lurasidone treatment. In summary, we provided new insights on the transcriptional changes relevant for the therapeutic intervention with lurasidone, which may ultimately promote resilience.
A statistical method for image-mediated association studies discovers genes and pathways associated with four brain disorders
2024, American Journal of Human Genetics
Brain imaging and genomics are critical tools enabling characterization of the genetic basis of brain disorders. However, imaging large cohorts is expensive and may be unavailable for legacy datasets used for genome-wide association studies (GWASs). Using an integrated feature selection/aggregation model, we developed an image-mediated association study (IMAS), which utilizes borrowed imaging/genomics data to conduct association mapping in legacy GWAS cohorts. By leveraging the UK Biobank image-derived phenotypes (IDPs), the IMAS discovered genetic bases underlying four neuropsychiatric disorders and verified them by analyzing annotations, pathways, and expression quantitative trait loci (eQTLs). A cerebellar-mediated mechanism was identified to be common to the four disorders. Simulations show that, if the goal is identifying genetic risk, our IMAS is more powerful than a hypothetical protocol in which the imaging results were available in the GWAS dataset. This implies the feasibility of reanalyzing legacy GWAS datasets without conducting additional imaging, yielding cost savings for integrated analysis of genetics and imaging.
Region-specific microRNA alterations in marmosets carrying SLC6A4 polymorphisms are associated with anxiety-like behavior: Marmoset SLC6A4 polymorphisms, anxiety and region-specific miRNAs
2022, eBioMedicine
Citation Excerpt :
In the adult brain, DCC may regulate synaptic functions, including synaptic plasticity.67 Increasing evidence highlights the link between DCC and psychiatric conditions with adolescence and adult onset68,69), especially depression.32,70 Furthermore, a recent genome-wide study on eight major psychiatric disorders identified DCC as the only genetic locus whose variants are associated with all eight disorders.5
Psychiatric diseases such as depression and anxiety are multifactorial conditions, highly prevalent in western societies. Human studies have identified a number of high-risk genetic variants for these diseases. Among them, polymorphisms in the promoter region of the serotonin transporter gene (SLC6A4) have attracted much attention. However, due to the paucity of experimental models, molecular alterations induced by these genetic variants and how they correlate to behavioral deficits have not been examined. In this regard, marmosets have emerged as a powerful model in translational neuroscience to investigate molecular underpinnings of complex behaviors.
Here, we took advantage of naturally occurring genetic polymorphisms in marmoset SLC6A4 gene that have been linked to anxiety-like behaviors. Using FACS-sorting, we profiled microRNA contents in different brain regions of genotyped and behaviorally-phenotyped marmosets.
We revealed that marmosets bearing different SLC6A4 variants exhibit distinct microRNAs signatures in a region of the prefrontal cortex whose activity has been consistently altered in patients with depression/anxiety. We also identified Deleted in Colorectal Cancer (DCC), a gene previously linked to these diseases, as a downstream target of the differently expressed microRNAs. Significantly, we showed that levels of both microRNAs and DCC in this region were highly correlated to anxiety-like behaviors.
Our findings establish links between genetic variants, molecular modifications in specific cortical regions and complex behavioral responses, providing new insights into gene-behavior relationships underlying human psychopathology.
This work was supported by France National Agency, NRJ Foundation, Celphedia and Fondation de France as well as the Wellcome Trust.
Differential DNA methylation in Black and White individuals with chronic low back pain enrich different genomic pathways
2022, Neurobiology of Pain
Citation Excerpt :
Gao et al., 2020) Chronic stress affects genes’ expression in Netrin and Wnt signaling pathways and has been associated with anxiety-like behavior, attention deficit hyperactivity disorder, insulin resistance, depressive symptoms, and increased blood pressure. ( Odaka et al., 2017; Yde Ohki et al., 2020; Torres-Berrío et al., 2020) Thus, it is plausible that higher levels of perceived stress (e.g., the stress of racial discrimination) induce alterations in Netrin and Wnt signaling pathways and result in higher cLBP outcomes in NHBs. Glutamate, γ-amino-butyric acid (GABA) Receptor Signaling, Opioid Signaling, Endocannabinoid Neuronal Synapse, and G-Protein Couple Receptor-Mediated Nutrient Sensing in Enteroendocrine cells pathways were over-represented.
Compared to Non-Hispanic Whites (NHWs), individuals who self-identify as Non-Hispanic Blacks (NHBs) in the United States experience more severe and disabling chronic low back pain (cLBP). We hypothesized that differences in DNA methylation (DNAm) play a role in racial disparities in cLBP.
To determine the relationship between DNAm levels and racial group differences in adults with cLBP. Our study’s secondary purpose was to perform a race-stratified comparison of adults with cLBP and pain-free controls and identify functional genomic pathways enriched by annotated differentially methylated genes.
We recruited 49 NHBs and 49 NHWs (49 cLBP and 49 pain-free controls, PFCs), analyzed DNAm from whole blood using reduced representation bisulfite sequencing, and identified enriched genomic pathways.
Among participants with cLBP, we identified 2873 differentially methylated loci (DML; methylation differences of at least 10% and p < 0.0001), many of which were annotated to genes of importance to pain pathology. These DMLs significantly enriched pathways to involved in nociception/pain processing (Dopamine-DARPP32 Feedback in cAMP signaling, GABA Receptor Signaling, Opioid Signaling) and neuronal differentiation (e.g., Calcium Signaling, Axon Guidance Signaling, and Endocannabinoid Neuronal Synapse). Our race stratified analyses of individuals with cLBP versus PFCs revealed 2356 DMLs in NHBs and 772 DMLs in NHWs with p < 0.0001 and > 10% methylation difference. Ingenuity Pathway Analysis revealed that many pathways of significance to pain such as Corticotropin Releasing Hormone Signaling, White Adipose Tissue Browning, and GABA Receptor Signaling pathways, were more significant in NHBs than NHWs.
Even though an individual’s self-identified race is a social construct, not a biological variable, racism associated with that classification affects virtually every aspect of life, including disease risk. DNAm induced alterations in stress signaling pathways may explain worse pain outcomes in NHBs.
Sex-Specific Role for SLIT1 in Regulating Stress Susceptibility
2022, Biological Psychiatry
Major depressive disorder is a pervasive and debilitating syndrome characterized by mood disturbances, anhedonia, and alterations in cognition. While the prevalence of major depressive disorder is twice as high for women as men, little is known about the molecular mechanisms that drive sex differences in depression susceptibility.
We discovered that SLIT1, a secreted protein essential for axonal navigation and molecular guidance during development, is downregulated in the adult ventromedial prefrontal cortex (vmPFC) of women with depression compared with healthy control subjects, but not in men with depression. This sex-specific downregulation of Slit1 was also observed in the vmPFC of mice exposed to chronic variable stress. To identify a causal, sex-specific role for SLIT1 in depression-related behavioral abnormalities, we performed knockdown (KD) of Slit1 expression in the vmPFC of male and female mice.
When combined with stress exposure, vmPFC Slit1 KD reflected the human condition by inducing a sex-specific increase in anxiety- and depression-related behaviors. Furthermore, we found that vmPFC Slit1 KD decreased the dendritic arborization of vmPFC pyramidal neurons and decreased the excitability of the neurons in female mice, effects not observed in males. RNA sequencing analysis of the vmPFC after Slit1 KD in female mice revealed an augmented transcriptional stress signature.
Together, our findings establish a crucial role for SLIT1 in regulating neurophysiological and transcriptional responses to stress within the female vmPFC and provide mechanistic insight into novel signaling pathways and molecular factors influencing sex differences in depression susceptibility.
Comparative analysis of hippocampal transcriptional features between major depressive disorder patients and animal models
2021, Journal of Affective Disorders
Citation Excerpt :
Increasing evidences have suggested that depression is related to axon damage (Miyata et al., 2016). Netrin-1 and its receptor DCC, which act as axon guidance cues to establish synaptic connections, have been found to be elevated in the cortex of MDD patients (Torres-Berrío et al., 2020). Chronic stress can reduce myelinated axons in the cortex and the density of axons in the striatum (Khan et al., 2019; Pittenger and Duman, 2008).
Major depressive disorder (MDD) is a psychiatric disorder caused by various etiologies. Chronic stress models are used to simulate the heterogeneous pathogenic processes of depression. However, few studies have compared transcriptional features between stress models and MDD patients.
We generated hippocampal transcriptional profiles of the chronic social defeat model by RNA sequencing and downloaded raw data of the same brain region from public databases of the chronic unpredictable mild stress model, the learned helplessness model, and MDD patients. Differential expression and gene co-expression analyses were integrated to compare transcriptional features between stress models and MDD patients.
Each stress model shared 11.4% to 16.3% of differentially expressed genes with MDD patients. Functional analysis at the gene expression level identified altered ensheathment of neurons in both stress models and MDD patients. At the gene network level, each stress model shared 20.9% to 41.6% of co-expressed genes with MDD patients. Functional analysis based on these genes found that axon guidance signaling is the most significantly enriched pathway that was shared by all stress models and MDD patients.
This study was limited by considering only a single brain region and a single sex of stress model animals.
Our results show that hippocampal transcriptional features of stress models partially overlap with those of MDD patients. The canonical pathways of MDD patients, including ensheathment of neurons, PTEN signaling, and axonal guidance signaling, were shared with all stress models. Our findings provide further clues to understand the molecular mechanisms of depression.

View all citing articles on Scopus

View full text

ReviewThe Netrin-1/DCC Guidance Cue Pathway as a Molecular Target in Depression: Translational Evidence

Abstract

Section snippets

The Netrin-1/DCC Signaling Pathway

Rodent Models of Stress Susceptibility

DCC Receptor Expression in the PFC Is Dysregulated in MDD and Determines Susceptibility to CSDS

Genetic Variants in NETRIN-1 and DCC Are Associated With MDD

Biomarkers of Vulnerability to MDD: Potential Role of miR-218

Conclusions and Future Directions

Acknowledgments and Disclosures

Lancet

Neurosci Biobehav Rev

Neurosci Biobehav Rev

Biol Psychiatry

Neuron

Dev Biol

Lancet Neurol

Prog Biophys Mol Biol

Trends Biochem Sci

Neuron

Neuron

Cell Rep

Cell Rep

Trends Neurosci

Neuron

Cell

Prog Brain Res

Neuroscience

Neurobiol Aging

Biol Psychiatry

J Biol Chem

Neurosci Biobehav Rev

Neurosci Biobehav Rev

Int J Dev Neurosci

Biol Psychiatry

Biol Psychiatry

Clin Psychol Rev

Prog Neuropsychopharmacol Biol Psychiatry

Neurobiol Stress

Cell

Biol Psychiatry

Neuropharmacology

Biol Psychiatry

Biol Psychiatry

Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication

Arch Gen Psychiatry

Characterizing developmental trajectories and the role of neuropsychiatric genetic risk variants in early-onset depression

JAMA Psychiatry

Why do many psychiatric disorders emerge during adolescence?

Nat Rev Neurosci

Age of onset of mental disorders: A review of recent literature

Curr Opin Psychiatry

Adolescent mental health—Opportunity and obligation

Science

The role of neural plasticity in depression: From hippocampus to prefrontal cortex

Neural Plast

Meta-analysis of cortical thickness abnormalities in medication-free patients with major depressive disorder

Neuropsychopharmacology

Synaptic plasticity and depression: New insights from stress and rapid-acting antidepressants

Nat Med

Decreased expression of synapse-related genes and loss of synapses in major depressive disorder

Nat Med

Synaptic dysfunction in depression: Potential therapeutic targets

Science

Understanding axon guidance: Are we nearly there yet?

Development

Making connections: Guidance cues and receptors at nonneural cell-cell junctions

Cold Spring Harb Perspect Biol

The growth cone cytoskeleton in axon outgrowth and guidance

Cold Spring Harb Perspect Biol

Netrins: Versatile extracellular cues with diverse functions

Development

Revisiting Netrin-1: One who guides (axons)

Front Cell Neurosci

Floor-plate-derived netrin-1 is dispensable for commissural axon guidance

Nature

Review
The Netrin-1/DCC Guidance Cue Pathway as a Molecular Target in Depression: Translational Evidence