The Netrin-1/DCC guidance system: dopamine pathway maturation and psychiatric disorders emerging in adolescence

Abstract

Axon guidance molecules direct growing axons toward their targets, assembling the intricate wiring of the nervous system. One of these molecules, Netrin-1, and its receptor, DCC (deleted in colorectal cancer), has profound effects, in laboratory animals, on the adolescent expansion of mesocorticolimbic pathways, particularly dopamine. Now, a rapidly growing literature suggests that (1) these same alterations could occur in humans, and (2) genetic variants in Netrin-1 and DCC are associated with depression, schizophrenia, and substance use. Together, these findings provide compelling evidence that Netrin-1 and DCC influence mesocorticolimbic-related psychopathological states that emerge during adolescence.

Further confirmation of netrin 1 receptor (DCC) as a depression risk gene via integrations of multi-omics data

“…Intriguingly, the DCC genomic region featured the most pleiotropic association (P meta = 4.26 × 10 −12 ) in this meta-analysis, exhibited significant associations with all eight diseases 90 . Additionally, previous studies have also highlighted DCC in mood instability and the risk of depression 57,[91][92][93] as well as schizophrenia 94 , and multiple in vitro and murine analyses have proven its potential impact on synaptic function. For example, the protein netrin-1 and its receptor (encoded by Dcc) are widely expressed in cortical neurons during synapse formation, with significant enrichment at synapses 83 .…”

“…DCC exhibited significant association signals in both SMR (P SMR-multi = 6.58 × 10 −5 in BrainSeq Phase 2, P SMR-multi = 1.27 × 10 −4 in CommonMind, P SMR-multi = 2.78 × 10 −5 in PsychENCODE) and iRIGS analyses (posterior probability = 0.828). DCC has been extensively described in a recent review regarding its potential roles in the central nervous systems and psychiatric disorders 57 , in brief, this gene is highly expressed in dendritic spines of pyramidal neurons, and exerts pivotal regulatory effects on synaptic function and plasticity in adult brain 58 . The Dcc protein is known to be a cell adhesion molecule that mediates the effects of netrin-1 on axon outgrowth [59][60][61] , and deficits of Dcc in the adult forebrain neurons results in aberrant long-term potentiation (LTP), long-term depression (LTD) and dendritic spine morphology, as well as impaired spatial and recognition 57,58 .…”

“…DCC has been extensively described in a recent review regarding its potential roles in the central nervous systems and psychiatric disorders 57 , in brief, this gene is highly expressed in dendritic spines of pyramidal neurons, and exerts pivotal regulatory effects on synaptic function and plasticity in adult brain 58 . The Dcc protein is known to be a cell adhesion molecule that mediates the effects of netrin-1 on axon outgrowth [59][60][61] , and deficits of Dcc in the adult forebrain neurons results in aberrant long-term potentiation (LTP), long-term depression (LTD) and dendritic spine morphology, as well as impaired spatial and recognition 57,58 . Intriguingly, recent studies have shown that DCC mRNA levels in the prefrontal cortex of antidepressant-free depression patients who committed suicide were significantly elevated comparing with control subjects (i.e., DCC mRNA levels were 48% higher in cases compared to control subjects in the first cohort by Manitt et al (p < 0.026) 62 , and were~40% higher in cases in comparison with controls in the second independent cohort by Torres-Berrío et al (p = 0.02) 63 ).…”

Extra-striatal D2/3 receptor availability in youth at risk for addiction

“…We measured extra-striatal DA 2/3 R availability in well-characterized youth who had been followed since birth. Participants were tested during their transition years to adulthood, a period of significant fronto-cortical pruning [46] and mesocortical DA pathway expansion [47]. It is also the developmental stage when drug and alcohol experimentation is most likely to escalate to problematic use.…”

<p>Targeting Netrin-1 and -4 as a Novel Diagnostic Parameter and Treatment Option for Diabetic Retinopathy</p>

“…13,14 Netrin-1 and -4 are the most known ligands of the family and critical axonal guidance protein during morphogenesis, embryonic development, and angiogenic processes. 15,16 Netrin-1 related axonal functions have been linked to two classes of receptors: the deleted in colorectal cancer (DCC) family, including DCC and its orthologue Neogenin-1, and the Unc5s family, including Unc5A 17,18 while Netrin-4 performs its activity majorly through binding to the laminin γ1 chain and disrupts laminin networks and basement membranes 15,16,19 (Figure 1).…”