The long-term goal of the proposed experiments is repair of neocortical projection neuron circuitry. This work aims toward the ultimate goal of repair by manipulation of endogenous neural progenitors in situ. This could lead to therapies for degenerative, developmental, or acquired diseases of cortex and its output circuitry (e.g. corticospinal). In neocortex, the effectiveness of such future therapies could depend critically on whether endogenous progenitors can be precisely induced to form the correct, subtype-specific neurons;differentiate and integrate appropriately;and re-form long-distance projections and complex functional connections. At the time of submission for the initial period of this grant, we had recently published (Magavi, Nature, 2000;Scharff, Neuron, 2000) the field's first demonstrations of induction of neurogenesis, the birth of new neurons, from endogenous progenitors in the adult brain. We chose corticothalamic projection neurons (CThPN) and their development for focused study in mice toward induction of neurogenesis because they are a prototypical population of long-distance cortical projection neurons, and because of their location closest to the available pool of caudal cortical SVZ progenitors. We hypothesized (now with substantial data during development and pilot adult data) that there exist partially fate-specified neocortical progenitors competent to differentiate into corticofugal neurons, including CThPN (Molyneaux, Neuron, 2005;Arlotta, Neuron, 2005;Molyneaux, Nat Rev NSci, 2007;Lai, Neuron, 2008;Joshi, Neuron, 2008;Azim, 2008). A next logical step toward future therapeutic manipulation of endogenous progenitors and induction of neurogenesis will be directed differentiation of specific neuron populations by manipulating combinatorial molecular-genetic controls. Though we have made considerable progress identifying cellular and molecular conditions that enable cortical neurogenesis and partial repair of adult cortical circuitry, many questions still remain to be investigated. These questions form the basis of the proposed research. Building on recent results, proposed experiments (Aim 1) functionally investigate FOG-2, a newly identified transcriptional regulator critical for CThPN development, using loss- and gain-of-function in vivo;
(Aim 2) investigate two new candidate combinatorial molecular-genetic controls over CThPN birth and development;
(Aim 3) investigate whether partially fate- restricted neural progenitors, recently identified during development, exist in the adult mouse neocortex, with potentially enhanced competence to generate corticofugal neurons;
and (Aim 4) induce CThPN neurogenesis from (potentially) partially fate-restricted progenitors in the adult mouse forebrain via manipulation of critical molecular-genetic controls over CThPN development. Together, these experiments will significantly advance our ability to induce type-specific neurogenesis and ultimately direct functional circuit repair of the adult CNS.

Public Health Relevance

Degenerative and traumatic neurological disorders are the source of great personal suffering and disability, and they account for a huge public health financial and social burden. Neural progenitors (sometimes termed neural stem cells) exist in the adult brain, and have been found in mice to be capable of generating a small number of new cerebral cortex nerve cells (neurons) under special conditions. Some adult progenitors might already be partially decided to generate types of neurons involved in human diseases. Knowledge of the molecular controls over the development and survival of the neurons that connect between specific centers of the brain, and the brain to the spinal cord, will provide new approaches for the treatment of neurodegenerative diseases involving cortical projection neurons, such as Huntington's disease (HD);corticospinal motor neuron degenerative diseases such as ALS, primary lateral sclerosis (PLS), and hereditary spastic paraplegia (HSP);and traumatic spinal cord injury. Building on recent work identifying defined progenitors and molecular controls over brain neuron birth and development, this project will investigate mechanisms by which the birth of new neurons (neurogenesis) can be induced in mice from (specific) progenitors already in the adult brain, toward design of therapeutic strategies to repair, modulate, or preserve injured or degenerating neurons in the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045523-11
Application #
8488489
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Owens, David F
Project Start
2002-08-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
11
Fiscal Year
2013
Total Cost
$349,614
Indirect Cost
$142,742
Name
Harvard University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Fame, Ryann M; MacDonald, Jessica L; Dunwoodie, Sally L et al. (2016) Cited2 Regulates Neocortical Layer II/III Generation and Somatosensory Callosal Projection Neuron Development and Connectivity. J Neurosci 36:6403-19
Woodworth, Mollie B; Greig, Luciano C; Liu, Kevin X et al. (2016) Ctip1 Regulates the Balance between Specification of Distinct Projection Neuron Subtypes in Deep Cortical Layers. Cell Rep 15:999-1012
Greig, Luciano C; Woodworth, Mollie B; Greppi, Chloé et al. (2016) Ctip1 Controls Acquisition of Sensory Area Identity and Establishment of Sensory Input Fields in the Developing Neocortex. Neuron 90:261-77
Galazo, Maria J; Emsley, Jason G; Macklis, Jeffrey D (2016) Corticothalamic Projection Neuron Development beyond Subtype Specification: Fog2 and Intersectional Controls Regulate Intraclass Neuronal Diversity. Neuron 91:90-106
Shipman, Seth L; Nivala, Jeff; Macklis, Jeffrey D et al. (2016) Molecular recordings by directed CRISPR spacer acquisition. Science 353:aaf1175
Fame, Ryann M; Dehay, Colette; Kennedy, Henry et al. (2016) Subtype-Specific Genes that Characterize Subpopulations of Callosal Projection Neurons in Mouse Identify Molecularly Homologous Populations in Macaque Cortex. Cereb Cortex :
Kishi, Noriyuki; MacDonald, Jessica L; Ye, Julia et al. (2016) Reduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice. Nat Commun 7:10520
Sances, Samuel; Bruijn, Lucie I; Chandran, Siddharthan et al. (2016) Modeling ALS with motor neurons derived from human induced pluripotent stem cells. Nat Neurosci 19:542-53
Jara, Javier H; Genç, Barış; Cox, Gregory A et al. (2015) Corticospinal Motor Neurons Are Susceptible to Increased ER Stress and Display Profound Degeneration in the Absence of UCHL1 Function. Cereb Cortex 25:4259-72
Sadegh, Cameron; Macklis, Jeffrey D (2014) Established monolayer differentiation of mouse embryonic stem cells generates heterogeneous neocortical-like neurons stalled at a stage equivalent to midcorticogenesis. J Comp Neurol 522:2691-706

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