Alivin 1, a Novel Neuronal Activity-Dependent Gene, Inhibits Apoptosis and Promotes Survival of Cerebellar Granule Neurons

Abstract

Neurons require Ca2+-dependent gene transcription for their activity-dependent survival, the mechanisms of which have not been fully elucidated yet. Here, we demonstrate that a novel primary response gene, alivin 1 (ali1), is an activity-dependent gene and promotes survival of neurons. Sequence analyses reveal that rat, mouse, and human Ali1 proteins contain seven leucine-rich repeats, one IgC2-like loop and a transmembrane domain, and display homology to Kek and Trk families. Expression of ali1 mRNA in cultured cerebellar granule neurons is rigidly regulated by KCl and/or NMDA concentrations in the culture medium and tightly correlated to depolarization-dependent survival and/or NMDA-dependent survival of the granule neuron. ali1 mRNA expression was regulated at the transcriptional step by the Ca2+ influx through voltage-dependent L-type Ca2+ channels when the cells were stimulated by 25 mm KCl. Expression of ali1 mRNA in cultured cortical neurons was inhibited when their spontaneous electrical activity was blocked by tetrodotoxin. Thus, the expression is neuronal activity dependent. Overexpression of Ali1 in cerebellar granule neurons inhibited apoptosis that was induced by the medium containing 5 mm KCl. The addition of anti-Ali1 antiserum or the soluble putative extracellular Ali1 domain to the 25 mm KCl-supported culture inhibited the survival of the granule neuron. These results suggest that expression of ali1 promotes depolarization-dependent survival of the granule neuron. Mouse ali1 was mapped to a locus approximately 55.3 cM from the centromere on chromosome 15 that is syntenic to positional candidate loci for familial Alzheimer's disease type 5 and Parkinson's disease 8 on human chromosome 12.

Detection, Validation, and Downstream Analysis of Allelic Variation in Gene Expression

“…The expression of Amigo2 was shown to promote the survival of cerebellar granule neurons and was considered a candidate for familial Alzheimer's disease type 5 (Ono et al 2003). We found the expression of Amigo2 to be highly correlated with the granule cell number in hippocampus (r ¼ À0.76, P , Figure 2).…”

Ion Channel Development, Spontaneous Activity, and Activity-Dependent Development in Nerve and Muscle Cells

“…Furthermore, survival is selective for neurons that are active synchronously with other neurons (601). Activity-dependent survival of cortical neurons requires Ca 2ϩ influx via voltage-gated Ca 2ϩ channels and/or NMDA receptors (196,465,577). Brain-derived neurotrophic factor (BDNF), parathyroid hormone-related peptide, and pituitary adenylate cyclase activating polypeptide (PACAP) have each been implicated as mediators of activity-dependent survival (196,309,464,577), which also seems to involve p38-mitogen-activated protein kinase, which phosphorylates and activates the transcription factor MEF2 (365).…”

Expressions and Roles of AMIGO Gene Family in Vascular Endothelial Cells

“…AMIGO-2 was independently identified by a different group using differential display screening for genes involved in depolarization and NMDA-dependent survival of cerebellar granule neurons and named alivin-1 (ali1) [9]. Over expression of alivin-1 in cerebellar granule neurons inhibited apoptosis induced by a low (5mM) KCl medium.…”