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.

LKB1-mediated spatial control of GSK3beta and adenomatous polyposis coli contributes to centrosomal forward movement and neuronal migration in the developing neocortex.

Neuronal migration is an essential process for the development of the cerebral cortex. We have previously shown that LKB1, an evolutionally conserved polarity kinase, plays a critical role in neuronal migration in the developing neocortex. Here we show that LKB1 mediates Ser9 phosphorylation of GSK3beta to inactivate the kinase at the leading process tip of migrating neurons in the developing neocortex. This enables the microtubule plus-end binding protein adenomatous polyposis coli (APC) to localize at the distal ends of microtubules in the tip, thereby stabilizing microtubules near the leading edge. We also show that LKB1 activity, Ser9 phosphorylation of GSK3beta, and APC binding to the distal ends of microtubules are required for the microtubule stabilization in the leading process tip, centrosomal forward movement, and neuronal migration. These findings suggest that LKB1-induced spatial control of GSK3beta and APC at the leading process tip mediates the stabilization of microtubules within the tip and is critical for centrosomal forward movement and neuronal migration in the developing neocortex.

Anterior cingulate inputs to nucleus accumbens control the social transfer of pain and analgesia.

Empathy is an essential component of social communication that involves experiencing others' sensory and emotional states. We observed that a brief social interaction with a mouse experiencing pain or morphine analgesia resulted in the transfer of these experiences to its social partner. Optogenetic manipulations demonstrated that the anterior cingulate cortex (ACC) and its projections to the nucleus accumbens (NAc) were selectively involved in the social transfer of both pain and analgesia. By contrast, the ACC→NAc circuit was not necessary for the social transfer of fear, which instead depended on ACC projections to the basolateral amygdala. These findings reveal that the ACC, a brain area strongly implicated in human empathic responses, mediates distinct forms of empathy in mice by influencing different downstream targets.

Protein 600 is a microtubule/endoplasmic reticulum-associated protein in CNS neurons.

There is an increasing body of literature pointing to cytoskeletal proteins as spatial organizers and interactors of organelles. In this study, we identified protein 600 (p600) as a novel microtubule-associated protein (MAP) developmentally regulated in neurons. p600 exhibits the unique feature to interact with the endoplasmic reticulum (ER). Silencing of p600 by RNA interference (RNAi) destabilizes neuronal processes in young primary neurons undergoing neurite extension and containing scarce staining of the ER marker Bip. Furthermore, in utero electroporation of p600 RNAi alters neuronal migration, a process that depends on synergistic actions of microtubule dynamics and ER functions. p600-depleted migrating neurons display thin, crooked, and "zigzag" leading process with very few ER membranes. Thus, p600 constitutes the only known MAP to associate with the ER in neurons, and this interaction may impact on multiple cellular processes ranging from neuronal development to neuronal maturation and plasticity.

LKB1 regulates neuronal migration and neuronal differentiation in the developing neocortex through centrosomal positioning.

The cerebral cortex is formed through the coordination of highly organized cellular processes such as neuronal migration and neuronal maturation. Polarity establishment of neurons and polarized regulation of the neuronal cytoskeleton are essential for these events. Here we find that LKB1, the closest homolog of the Caenorhabditis elegans polarity protein Par4, is expressed in the developing neocortex. Knock-down of LKB1 in migrating immature neurons impairs neuronal migration, with alteration of the centrosomal positioning and with uncoupling between the centrosome and nucleus. Furthermore, impairment of LKB1 in differentiating neurons within the cortical plate induces malpositioning of the centrosome at the basal side of the nucleus, instead of the normal apical positioning. This is accompanied with the disruption of axonal and dendritic polarity, resulting in reversed orientation of differentiating neurons. Moreover, LKB1 specifies axon and dendrites identity in vitro. Together, these observations indicate that LKB1 plays a critical role in neuronal migration and neuronal differentiation. Furthermore, we propose that proper neuronal migration and differentiation are intimately coupled to the precise control of the centrosomal positioning/movement directed by LKB1.

p600 regulates spindle orientation in apical neural progenitors and contributes to neurogenesis in the developing neocortex.

Apical neural progenitors (aNPs) drive neurogenesis by means of a program consisting of self-proliferative and neurogenic divisions. The balance between these two manners of division sustains the pool of apical progenitors into late neurogenesis, thereby ensuring their availability to populate the brain with terminal cell types. Using knockout and in utero electroporation mouse models, we report a key role for the microtubule-associated protein 600 (p600) in the regulation of spindle orientation in aNPs, a cellular event that has been associated with cell fate and neurogenesis. We find that p600 interacts directly with the neurogenic protein Ndel1 and that aNPs knockout for p600, depleted of p600 by shRNA or expressing a Ndel1-binding p600 fragment all display randomized spindle orientation. Depletion of p600 by shRNA or expression of the Ndel1-binding p600 fragment also results in a decreased number of Pax6-positive aNPs and an increased number of Tbr2-positive basal progenitors destined to become neurons. These Pax6-positive aNPs display a tilted mitotic spindle. In mice wherein p600 is ablated in progenitors, the production of neurons is significantly impaired and this defect is associated with microcephaly. We propose a working model in which p600 controls spindle orientation in aNPs and discuss its implication for neurogenesis.