Cancer-Linked Gene Involved in Neuronal Migration
Danielle Stanton-Turcotte, Karolynn Hsu, Samantha A. Moore, Makiko Yamada, James P. Fawcett, et al.
(see pages 3931–3948)
MLLT11 is a 90 aa protein that was first identified because its gene was translocated and fused to the mixed-lineage leukemia (MLL) gene in two children with pediatric leukemia. MLLT11 has since been linked to several other cancers and has been shown to promote differentiation of hematopoietic precursors into T cells. Remarkably, the only other cell types that express MLLT11 are neurons of the PNS and CNS. The role of MLLT11 in neurons has been unknown, but Stanton-Turcotte et al. report that it contributes to migration and neurite outgrowth of cortical neurons.
Expression of MLLT11 in the developing cerebral cortex increased as upper-layer pyramidal cells were generated and were beginning to migrate through the intermediate zone and lower layers of the cortical plate. Expression increased in the upper layers as they became populated with neurons, and expression declined starting around postnatal day 21. Knocking out MLLT11 selectively in newborn upper-layer neurons led to cortical thinning, and it slowed migration of upper-layer neurons. In contrast, overexpressing MLLT11 accelerated neuronal migration into the cortical plate. Knocking out MLLT11 also reduced neurite growth: upper-layer pyramidal neurons send projections to the contralateral hemisphere through the corpus callosum, and this structure was significantly smaller in MLLT11-deficient mice than in controls. And the dendritic arbors of MLLT11-deficient upper-layer pyramidal neurons were shorter and had fewer branches than normal.
Pull-down assays revealed that MLLT11 was associated with several tubulin and myosin isoforms. Furthermore, MLLT11 colocalized with acetylated (stabilized) tubulin in cultured neurons. Notably, both neuronal migration and process extension depend strongly on microtubule dynamics. Therefore, MLLT11 may promote migration and neurite outgrowth by regulating microtubule stability. Stimulation of migration and process extension may also explain the link between MLLT11 and cancers, as these processes contribute to tissue invasion and metastasis of tumor cells.
Dendrites are longer and more highly branched in neurons cultured from control mice (top) than in neurons from MLLT11-deficient mice (bottom). See Stanton-Turcotte et al. for details.
Hippocampal Metabolites Linked to Enhancers of Cognition
Shweta Gupta, Arturo J. Moreno, Dan Wang, Julio Leon, Chen Chen, et al.
(see pages 4016–4025)
Cognitive function is influenced by numerous neuromodulators, immune-system molecules, and circulating hormones. One such hormone is α-klotho, a protein produced predominantly in the kidneys, and to a lesser extent by the choroid plexus. As a transmembrane protein, klotho acts as a coreceptor for FGF23, which regulates phosphate levels in the blood. But the extracellular domain of klotho can be shed through cleavage to produce a soluble hormone, which is carried in blood and CSF and exerts effects throughout the body. Klotho levels decline with age, and systemic administration of the soluble hormone enhances cognitive function and long-term potentiation in mice. How klotho exerts its effects in the brain is unclear, however. To address this question, Gupta et al. examined the metabolic profile of hippocampi from mice treated with either the entire extracellular domain of klotho or one of its subdomains (KL1). They compared these metabolic profiles to that of hippocampi of mice provided with cognitive stimulation—another treatment known to improve cognitive function.
Hippocampal concentrations of 154 metabolites from 42 metabolic pathways were quantified using liquid chromatography tandem mass spectrometry. Principal components analysis showed that the metabolic profiles of hippocampi of mice that had explored a Y maze were distinct from those of mice that had stayed in their home cages. Specifically, levels of 75 metabolites were higher and levels of 2 metabolites were lower in cognitively stimulated mice than in controls. Administration of klotho or KL1 also altered hippocampal metabolism, and the affected metabolites partially overlapped with those altered by cognitive stimulation. Moreover, a metabolic score based on levels of metabolites upregulated in the three conditions was correlated with performance on a spatial recognition task. Pathway analyses indicated that these shared metabolites were related to amino acid and purine metabolism.
These results suggest that cognitive stimulation and klotho treatment induce partially overlapping metabolic pathways in the hippocampus and that stimulation of these pathways is associated with enhanced recognition memory. Notably, some of the elevated metabolites, including serine, citrulline, and riboflavin, have previously been linked to synaptic plasticity and cognition. Future work will need to detail how specific metabolic pathways are activated by these treatments and how they contribute to cognitive performance.
Footnotes
This Week in The Journal was written by Teresa Esch, Ph.D.
