Impaired subgranular zone radial glia morphology and transient amplification of neural progenitors in Mllt11-deficient mice leads to increased hippocampal neurogenesis

Abstract

The mammalian hippocampus derives from the cortical hem region of the forebrain and is one of the two regions in the mammalian forebrain that contains neural progenitors capable of generating new neurons in the postnatal brain. Hippocampal neural stem cells, referred to as type I progenitors, are Sox2+/GFAP+, localize along the hilar boundary region, and possess a radial glia fiber that spans the thickness of the dentate gurus. The hilar boundary region serves as a niche for the neural progenitor pool, controlling the activation of type-1 progenitors to transit amplifying type-2 neural progenitors which lose their apical adherence to the hilus as they differentiate to granule cells. The genetic regulation of this process is not fully understood and requires factors that control the mobilization of type-1 cells from their hilar niche in the subgranular zone. To that end we now report a role for Mllt11 (Af1q/Tcf7c; Myeloid/lymphoid or mixed-lineage leukemia; translocated to chromosome 11/All1 Fused Gene from Chromosome 1q/T cell factor 7 co-factor), a regulator of neurite formation and migration in the cortex, in the regulation of hippocampal neurogenesis by restricting the transition of type-1 cells to transit amplifiers and neuroblasts. We previously showed that Cux2 (Cutl2) is widely expressed in the developing hippocampus, initially in the subventricular zone of the cortical hem, which generates the dentate gyrus, then in both type-1 and type-2 neural progenitors, and later in maturing granule cells of the perinatal hippocampus. To evaluate a role for Mllt11 in hippocampal neurogenesis, we used a Cux2IRESCre/+ line to generate a Mllt11 loss-of-function in perinatal hippocampal progenitors and differentiating granule cells. The loss of Mllt11 led to enlarged dentate blades dues to increased generation of NeuN+ and Calbindin+ granule cells. Explorations of the progenitor pool revealed increased transit amplifying cells due to an expanded pool of displaced Sox2+/GFAP+ deep in the dentate blades, with altered radial glial morphology. Consequently, type-1 progenitors aberrantly transitioned to amplifying progenitors and neuroblasts, resulting in enhanced granule cell neurogenesis in the postnatal hippocampus. Primary neurosphere formation assays confirmed enhanced proliferation of neural stem cells derived from Mllt11 knockout hippocampi. Taken together, the findings reported here demonstrate the critical role of Mllt11 in maintaining the hippocampal radial glial phenotype and their association within the subgranular zone-hilar niche boundary region, thereby controlling their differentiation to transit amplifiers and granule cells.