A notable determinant of human intellectual capacity is the enormous size and complexity of our neocortex. The neocortex forms during embryogenesis and then expands during fetal development when progenitors differentiate to populate the cortical plate. Defects in brain growth and morphogenesis result in a host of neurodevelopmental disorders, neuropsychiatric diseases, and intellectual disabilities. A key step towards understanding the normal and abnormal functions of the brain thus lies in defining the mechanisms driving neocortical growth. Progress towards this goal has been made though the identification of functionally distinct neural progenitor populations, most prominently ventricular radial glia (vRG), intermediate progenitor (IP), and basal/outer radial glia (bRG) cell. These classes of progenitors are common to both rodents and humans. However, recent studies have proposed that the neocortical enlargement and complexity seen in humans may result in part from a substantial increase in the genesis of bRG and IP cells that is not seen in rodents. Remarkably little is known about the mechanisms behind this human-specific expansion. Our preliminary experiments implicate Foxp transcription factors as important components to this process. Foxp1 and Foxp4 are expressed in the human neocortex as vRG cells transform into bRG and IP cells, and altering Foxp1 and Foxp4 functions in mouse changes cortical development in a manner suggesting that they play pivotal roles controlling the production of bRG and IP cells respectively. In this proposal, we will determine the function of Foxp proteins in both mouse and human cortical development.
In Aim 1 we will characterize the expression of Foxp proteins in the developing mouse and human neocortex.
In Aim 2, we will determine how manipulation of Foxp functions alters the generation of bRG and IP cells, and the overall size and structure of the cerebral cortex. Lastly, in Aim 3 we will define the genomic targets of Foxp proteins mediating their contributions to neocortical growth.
The remarkable information processing capacity of the human brain is thought to derive from its enormous mass, cellular density, and structural complexity. The proposed studies seek to identify the genetic factors that regulate the formation and function of the neural stem and progenitors that promote human brain growth. Through these studies we will gain novel insights into the mechanisms that underpin the evolution of brain structures and the underlying causes of a variety of neurodevelopmental disorders.
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