INVESTIGATING THE ROLE OF MLLT11 IN CORTICAL DEVELOPMENT

Abstract

The formation of connections within the mammalian neocortex is highly regulated by both extracellular guidance mechanisms and intrinsic gene expression programs. Dysregulation of these programs has been shown to cause a variety of neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD). The regulation of cortical projection morphologies and how their misregulation contributes to NDDs is not yet fully understood at the molecular level. Here, I report a role for Mllt11 (Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene From Chromosome 1q) in the migration and neurite outgrowth of callosal projection neurons during mouse brain formation. I show that Mllt11 expression is exclusive to developing neurons and is enriched in the developing cortical plate (CP) during the formation of the superficial cortical layers. In cultured primary cortical neurons, Mllt11 is detected in varicosities and growth cones as well as the soma. Using conditional loss-of-function and gain-of-function analysis I show that Mllt11 is required for neuritogenesis and proper migration of upper layer (UL) cortical projection neurons (CPNs). Loss of Mllt11 in the superficial cortex of male and female neonates leads to a severe reduction in fibres crossing the corpus callosum (CC), a progressive loss in the maintenance of UL CPN gene expression, and reduced complexity of dendritic arborization. Proteomic analysis revealed that Mllt11 associates with stabilized microtubules and motor proteins. Additionally, loss of Mllt11 resulted in a spectrum of mild behavioral deficits similar to those seen in human cases of ASD as well as mouse models of NDDs, which varied by sex and number of intact copies of the Mllt11 allele. Taken together, our findings support a role for Mllt11 in promoting the formation of mature UL CPN morphologies and connectivity in the cerebral cortex.