This Week in The Journal

Abstract

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 StantonTurcotte 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 andmetastasis of tumor cells.