AMP-activated protein kinase regulates cytoplasmic dynein behavior and contributes to neuronal migration in the developing neocortex.

The microtubule motor cytoplasmic dynein contributes to radial migration of newborn pyramidal neurons in the developing neocortex. Here, we show that AMP-activated protein kinase (AMPK) mediates the nucleus-centrosome coupling, a key process for radial neuronal migration that relies on dynein. Depletion of the catalytic subunit of AMPK in migrating neurons impairs this coupling as well as neuronal migration. AMPK shows overlapping subcellular distribution with cytoplasmic dynein and the two proteins interact with each other. Pharmacological inhibition or activation of AMPK modifies the phosphorylation states of dynein intermediate chain (DIC) and dynein functions. Furthermore, AMPK phosphorylates DIC at Ser81. Expression of a phospho-resistant mutant of DIC retards neuronal migration in a similar way to AMPK depletion. Conversely, expression of the phospho-mimetic mutant of DIC alleviates impaired neuronal migration caused by AMPK depletion. Thus, AMPK-regulated dynein function via Ser81 DIC phosphorylation is crucial for radial neuronal migration.

Splicing factors control C. elegans behavioural learning in a single neuron by producing DAF-2c receptor.

Alternative splicing generates protein diversity essential for neuronal properties. However, the precise mechanisms underlying this process and its relevance to physiological and behavioural functions are poorly understood. To address these issues, we focused on a cassette exon of the Caenorhabditis elegans insulin receptor gene daf-2, whose proper variant expression in the taste receptor neuron ASER is critical for taste-avoidance learning. We show that inclusion of daf-2 exon 11.5 is restricted to specific neuron types, including ASER, and is controlled by a combinatorial action of evolutionarily conserved alternative splicing factors, RBFOX, CELF and PTB families of proteins. Mutations of these factors cause a learning defect, and this defect is relieved by DAF-2c (exon 11.5+) isoform expression only in a single neuron ASER. Our results provide evidence that alternative splicing regulation of a single critical gene in a single critical neuron is essential for learning ability in an organism.

Role of synaptic phosphatidylinositol 3-kinase in a behavioral learning response in C. elegans.

The phosphatidylinositol 3-kinase (PI3K) pathway regulates many cellular functions, but its roles in the nervous system are still poorly understood. We found that a newly discovered insulin receptor isoform, DAF-2c, is translocated from the cell body to the synaptic region of the chemosensory neuron in Caenorhabditis elegans by a conditioning stimulus that induces taste avoidance learning. This translocation is essential for learning and is dependent on the mitogen-activated protein kinase-regulated interaction of CASY-1 (the calsyntenin ortholog) and kinesin-1. The PI3K pathway is required downstream of the receptor. Light-regulated activation of PI3K in the synaptic region, but not in other parts of the cell, switched taste-attractive behavior to taste avoidance, mimicking the effect of conditioning. Thus, synaptic PI3K is crucial for the behavioral switch caused by learning.