Currently there is no successful treatment that restores damaged brain circuitry. Neuron loss by either
neurodegenerative diseases or trauma causes neurological and cognitive dysfunction, posing a great burden for
human health. There is a critical need to find strategies for neural circuit repair. Direct reprogramming
approaches hold great promise for brain repair. Their success in functional circuit restoration will depend on their
capacity to convert other cells into neurons with functions matching those of the neurons damaged in a circuit.
This precise conversion has been observed in the mouse cerebral cortex between cortical output (corticofugal)
neurons, which can acquire the connectivity properties, including long-range projections, typical of other
corticofugal subtypes. Though this is a promising step forward toward circuit repair, this precise conversion has
been observed when reprogramming is induced at embryonic or immature states.
The mechanisms that preclude reprogramming in differentiated neurons or the mechanisms that keep neuron
identity unchanged throughout life are not understood. Hence, our goal is to investigate mechanisms critical for
maintaining neuron subtype identity in differentiated neurons and determine how they limit reprogramming over
time. This will reveal barriers that preclude functional conversion between neuron subtypes in vivo. We propose
to investigate these mechanisms in corticofugal neurons, specifically in the context of in vivo reprogramming of
Corticothalamic neurons (CTn) to produce Subcerebral projection neurons (SCn), a clinically relevant neuron
subtype that degenerates in Amyotrophic lateral sclerosis and whose axons are damaged by spinal cord injury.
In this proposal we will investigate whether identity maintenance mechanisms can be manipulated for in vivo
reprogramming of CTn into functional SCn (Aim 1), we will determine whether these mechanisms can be
inactivated in mature CTn to eliminate barriers that preclude CTn conversion into SCn (Aim 2), and we will
elucidate the underlying downstream signals that preclude conversion of CTn into SCn in vivo (Aim 3).