L1 cell adhesion molecule promotes resistance to alcohol-induced silencing of growth cone responses to guidance cues.

Alcohol exposure in utero is a common cause of mental retardation, but the targets and mechanisms of action are poorly understood. Several lines of data point toward alterations in cortical connectivity, suggesting that axon guidance may be vulnerable to alcohol exposure. To test this, we asked whether ethanol directly affects cortical axonal growth cone responses to guidance cues. We find that even low concentrations of ethanol (12.5 mM; 57.2 mg/dl) commonly observed in social drinking prevent growth cone responses to three mechanistically independent guidance cues, Semaphorin3A, Lysophosphatidic Acid, and Netrin-1. However, this effect is highly dependent on substrate; axonal growth cones extending on an L1 cell adhesion molecule (L1CAM) substrate retain responsiveness to cues following exposure to ethanol, while those growing on poly-L-lysine or N-cadherin do not. The effects of ethanol on axon extension are, by contrast, quite modest. Quantitative assessments of the effects of ethanol on the surface distribution of L1CAM in growth cones suggest that L1CAM homophilic interactions may be particularly relevant for retaining growth cone responsiveness following ethanol exposure. Together, our findings indicate that ethanol can directly and generally alter growth cone responses to guidance cues, that a substrate of L1CAM effectively antagonizes this effect, and that cortical axonal growth cone vulnerability to ethanol may be predicted in part based on the environment through which they are extending.

Granins as disease-biomarkers: translational potential for psychiatric and neurological disorders.

The identification of biomarkers represents a fundamental medical advance that can lead to an improved understanding of disease pathogenesis, and holds the potential to define surrogate diagnostic and prognostic endpoints. Because of the inherent difficulties in assessing brain function in patients and objectively identifying neurological and cognitive/emotional symptoms, future application of biomarkers to neurological and psychiatric disorders is extremely desirable. This article discusses the biomarker potential of the granin family, a group of acidic proteins present in the secretory granules of a wide variety of endocrine, neuronal and neuroendocrine cells: chromogranin A (CgA), CgB, Secretogranin II (SgII), SgIII, HISL-19 antigen, 7B2, NESP55, VGF and ProSAAS. Their relative abundance, functional significance, and secretion into the cerebrospinal fluid (CSF), saliva, and the general circulation have made granins tractable targets as biomarkers for many diseases of neuronal and endocrine origin, recently impacting diagnosis of a number of neurological and psychiatric disorders including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, and schizophrenia. Although research has not yet validated the clinical utility of granins as surrogate endpoints for the progression or treatment of neurological or psychiatric disease, a growing body of experimental evidence indicates that the use of granins as biomarkers might be of great potential clinical interest. Advances that further elucidate the mechanism(s) of action of granins, coupled with improvements in biomarker technology and direct clinical application, should increase the translational effectiveness of this family of proteins in disease diagnosis and drug discovery.

Effects of ethanol on axon outgrowth and branching in developing rat cortical neurons.

Humans exposed prenatally to ethanol can exhibit brain abnormalities and cognitive impairment similar to those seen in patients expressing mutant forms of the L1 cell adhesion molecule (L1CAM). The resemblance suggests that L1CAM may be a target for ethanol, and consistent with this idea, ethanol can inhibit L1CAM adhesion in cell lines and L1CAM-mediated outgrowth and signaling in cerebellar granule neurons. However, it is not known whether ethanol inhibits L1CAM function in other neuron types known to require L1CAM for appropriate development. Here we asked whether ethanol alters L1CAM function in neurons of the rat cerebral cortex. We find that ethanol does not alter axonal polarization, L1CAM-dependent axon outgrowth or branching, or L1CAM recycling in axonal growth cones. Thus, ethanol inhibition of L1CAM is highly dependent on neuronal context.

Expression of VGF mRNA in developing neuroendocrine and endocrine tissues.

Analysis of knockout mice suggests that the neurotropin-inducible secreted polypeptide VGF (non-acronymic) plays an important role in the regulation of energy balance. VGF is synthesized by neurons in the central and peripheral nervous systems (CNS, PNS), as well as in the adult pituitary, adrenal medulla, endocrine cells of the stomach and pancreatic beta cells. Thus VGF, like cholecystokinin, leptin, ghrelin and other peptide hormones that have been shown to regulate feeding and energy expenditure, is synthesized in both the gut and the brain. Although detailed developmental studies of VGF localization in the CNS and PNS have been completed, little is known about the ontogeny of VGF expression in endocrine and neuroendocrine tIssues. Here, we report that VGF mRNA is detectable as early as embryonic day 15.5 in the developing rat gastrointestinal and esophageal lumen, pancreas, adrenal, and pituitary, and we further demonstrate that VGF mRNA is synthesized in the gravid rat uterus, together supporting possible functional roles for this polypeptide outside the nervous system and in the enteric plexus.