Axonal Growth of Midbrain Dopamine Neurons is Modulated by the Cell Adhesion Molecule ALCAM Through Trans-Heterophilic Interactions with L1cam, Chl1, and Semaphorins

Abstract

The growth of axons corresponding to different neuronal subtypes is governed by unique expression profiles of molecules on the growth cone. These molecules respond to extracellular cues either locally though cell adhesion interactions or over long distances through diffusible gradients. Here, we report that that the cell adhesion molecule ALCAM (CD166) can act as an extracellular substrate to selectively promote the growth of murine midbrain dopamine (mDA) neuron axons through a trans-heterophilic interaction with mDA-bound adhesion molecules. In mixed-sex primary midbrain cultures, the growth-promoting effect of ALCAM was abolished by neutralizing antibodies for components of the Semaphorin receptor complex Nrp1, Chl1, or L1cam. The ALCAM substrate was also found to modulate the response of mDA neurites to soluble semaphorins in a context-specific manner by abolishing the growth-promoting effect of Sema3A but inducing a branching response in the presence of Sema3C. These findings identify a previously unrecognized guidance mechanism whereby cell adhesion molecules act in trans to modulate the response of axonal growth cones to soluble gradients to selectively orchestrate the growth and guidance of mDA neurons.

Genetics of physiological dysregulation: findings from the long life family study using joint models

“…We found that in most cases axonal guidance was among the top biological processes enriched for the 36 genes associated with the rate of increase in physiological dysregulation with age (DM-RS) (see examples in Supplementary Figure 5). These results were further supported by the information provided by NCBI Gene (https://www.ncbi.nlm.nih.gov/gene/) about biological effects of these 36 genes, and relevant research publications (e.g., [49][50][51]).…”

DNA methylation changes following narrative exposure therapy in a randomized controlled trial with female former child soldiers

“…Actin dynamics interact with several of the identified enriched gene networks, namely glutaminergic signalling, focal adhesion, ECM-receptor interaction (see review by Rudy 39 ) as well as the RAP1 signalling pathway 40 . ALCAM is a member of the immunoglobulin superfamily and important for the growth of midbrain dopamine neurons through trans-heterophilic interactions 41 , 42 . Dopamine neurons in the midbrain are crucial for reinforcement learning (see review by Daw et al 43 ).…”

Genome-Wide Polygenic Risk Score Identifies Individuals at Elevated Parkinson’s Disease Risk

“…Another recent study of pleiotropic genetic risk factors identified 17 loci which are shared risk factors for Parkinson disease and type 1 diabetes, Crohn's disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis [29]. In addition, cellular adhesion molecules, which was found to be among the pathways enriched for among the identified genes, has also attracted recent attention for a possible significance in PD [30], further highlighting the novelty and importance of pathways identified through polygenetic risk stratification by PD-GPRS.…”