Paola Arlotta, PhD
During embryonic development, neural progenitors undergo precise differentiation to generate the amazing variety of neuronal types that ultimately populate the mature brain. While some of the basic mechanisms that control general aspects of progenitor specification into neurons have been defined, the genetic programs that control the differentiation of distinct types of neurons in the brain are still largely unknown.
In our lab we address this issue in the mammalian cerebral cortex and our main interest focuses on understanding and investigating the molecular pathways that direct the early specification of progenitors to generate distinct types of projection neurons during development. We specifically focus on the early signals that induce differentiation of corticospinal neurons, a clinically relevant neuronal target population that in humans selectively degenerates in ALS (Lou Gehrig's disease), Hereditary Spastic Paraplegia (HSP), Primary Lateral Sclerosis (PLS), and that is permanently injured in spinal cord injury.
Studies aimed at investigating the molecular controls over the generation of individual neuron types have been difficult in the nervous system due to the astonishing variety of neurons that populate this tissue, in combination with the difficulty to distinguish, and thus study, one neuron type in isolation from others. While this is true for many neuron types, we have previously identified a large set of genes that in specific combinations can be used to uniquely identify the lineage of corticospinal neurons, and therefore provide us with a great resource to investigate the molecular development of this individual neuron type in vivo.
In order to understand whether during corticogenesis specific progenitors exists which are fated to generate corticospinal neurons, we are currently using selected combinations of corticospinal "early genes" to generate new genetic mouse models in which expression of CreERT2 and Flpe recombinases are targeted to the prospective progenitors of the corticospinal lineage. Our aim is to genetically fate map and identify progenitors/early post-mitotic neurons of this neuronal lineage in order to both define the timing of lineage specification and fate restriction in vivo, and to understand the signals that determine progenitor commitment to generate corticospinal neurons. In related work, we also apply a combination of approaches including ultrasound-guided injection in the developing embryo, in utero electroporation and FACS purification of distinct neuron types to manipulate cortical progenitors in vivo, as well as molecular profiling methods to identify key transcriptional, epigenetic and proteomic changes that instruct neuronal lineage selection to form corticospinal neurons.
In the long run, we believe that understanding the molecular signals that instruct corticospinal neuron birth and differentiation during development has great potential to inform future experiments that manipulate these exact molecular signals to induce stem cells to generate corticospinal neurons for cell replacement therapy in neurodegenerative diseases.