Investigating the role of MLLT11 in the development of cortical hem derivatives and hippocampal neurogenesis

Abstract

The mammalian Cortical Hem plays a key role in orchestrating the formation of Cajal-Retzius cells, the Choroid Plexus, and hippocampus, a structure crucial to cognition and spatial learning. While several key regulators of Cortical Hem development have been identified, the downstream processes they regulate have remained obscure. This thesis explores the role of Mllt11, originally viewed as only an oncogenic factor, in the development of the Cortical Hem and the Dentate Gyrus region of the hippocampus. This is the first study to report the expression of Mllt11 in postnatal and adult mouse hippocampus and provides insights into its function in the developing Cortical Hem region and its derivatives. Through use of a genetic Cre-lox strategy, the Mllt11 gene was conditionally ablated from cells in the developing Cortical Hem and hippocampus. Part of the genetic strategy involved activating the expression of the fluorescence reporter gene tdTomato within the same cells that lacked Mllt11, to monitor the behaviour of mutant cells. The loss of Mllt11 disrupted the formation of tissues derived from the Cortical Hem, including Cajal-Retzius cells and the lateral ventricular Choroid Plexus. Furthermore, Mllt11 loss greatly impacted hippocampal neurogenesis, in part due to the aberrant position of type-1 radial glial progenitors within the developing Dentate Gyrus. As a consequence, type-1 progenitors rapidly transitioned to amplifying neural progenitors and neuroblasts, which ultimately enhanced formation of immature granule cells in the postnatal hippocampus. Taken together, the findings reported herein demonstrate the critical role of Mllt11 in maintaining the hippocampal radial glial phenotype and the balance between neural progenitor proliferation and terminal differentiation. It is also demonstrated that Mllt11 is required for the proper migration of neural progenitors to fuel the growth of the Choroid Plexus, and invasion of Cajal-Retzius cells into the pallial neocortex.