Expression of Gas1 in Mouse Brain: Release and Role in Neuronal Differentiation.

Growth arrest-specific 1 (Gas1) is a pleiotropic protein that induces apoptosis of tumor cells and has important roles during development. Recently, the presence of two forms of Gas1 was reported: one attached to the cell membrane by a GPI anchor; and a soluble extracellular form shed by cells. Previously, we showed that Gas1 is expressed in different areas of the adult mouse CNS. Here, we report the levels of Gas1 mRNA protein in different regions and analyzed its expressions in glutamatergic, GABAergic, and dopaminergic neurons. We found that Gas1 is expressed in GABAergic and glutamatergic neurons in the Purkinje-molecular layer of the cerebellum, hippocampus, thalamus, and fastigial nucleus, as well as in dopaminergic neurons of the substantia nigra. In all cases, Gas1 was found in the cell bodies, but not in the neuropil. The Purkinje and the molecular layers show the highest levels of Gas1, whereas the granule cell layer has low levels. Moreover, we detected the expression and release of Gas1 from primary cultures of Purkinje cells and from hippocampal neurons as well as from neuronal cell lines, but not from cerebellar granular cells. In addition, using SH-SY5Y cells differentiated with retinoic acid as a neuronal model, we found that extracellular Gas1 promotes neurite outgrowth, increases the levels of tyrosine hydroxylase, and stimulates the inhibition of GSK3ß. These findings demonstrate that Gas1 is expressed and released by neurons and promotes differentiation, suggesting an important role for Gas1 in cellular signaling in the CNS.

The absence of the aryl hydrocarbon receptor in the R6/1 transgenic mouse model of Huntington's disease improves the neurological phenotype.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an abnormal CAG repeat expansion in the huntingtin gene coding for a protein with an elongated polyglutamine sequence. HD patients present choreiform movements, which are caused by the loss of neurons in the striatum and cerebral cortex. Previous reports indicate that the absence of the aryl hydrocarbon receptor (AhR) protects mice from excitotoxic insults and increases the transcription of neurotrophic factors. Based on these data, we evaluated the effects of the lack of the AhR on a mice model of HD, generating a double transgenic mouse, expressing human mutated huntingtin (R6/1 mice) and knockout for the AhR. Our results show that the body weight of 30-week-old double transgenic mice is similar to that of R6/1 mice; however, feet clasping, an indicative of neuronal damage in the R6/1 animals, was not observed. In addition, motor coordination and ambulatory behavior in double transgenic mice did not deteriorate over time as occur in the R6/1 mice. Moreover, the anxiety behavior of double transgenic mice was similar to wild type mice. Interestingly, astrogliosis is also reduced in the double transgenic mice. The present data demonstrate that the complete loss of the AhR reduces the motor and behavioral deterioration observed in R6/1 mice, suggesting that the pharmacological modulation of the AhR could be a therapeutic target in HD.