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.
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.
|Wuttke, Thomas V; Markopoulos, Foivos; Padmanabhan, Hari et al. (2018) Developmentally primed cortical neurons maintain fidelity of differentiation and establish appropriate functional connectivity after transplantation. Nat Neurosci 21:517-529|
|Rodriguez-Muela, Natalia; Litterman, Nadia K; Norabuena, Erika M et al. (2017) Single-Cell Analysis of SMN Reveals Its Broader Role in Neuromuscular Disease. Cell Rep 18:1484-1498|
|Itoh, Yasuhiro; Poulopoulos, Alexandros; Macklis, Jeffrey D (2017) Unfolding the Folding Problem of the Cerebral Cortex: Movin' and Groovin'. Dev Cell 41:332-334|
|Fame, Ryann M; Dehay, Colette; Kennedy, Henry et al. (2017) Subtype-Specific Genes that Characterize Subpopulations of Callosal Projection Neurons in Mouse Identify Molecularly Homologous Populations in Macaque Cortex. Cereb Cortex 27:1817-1830|
|Shipman, Seth L; Nivala, Jeff; Macklis, Jeffrey D et al. (2017) CRISPR-Cas encoding of a digital movie into the genomes of a population of living bacteria. Nature 547:345-349|
|Chen, Zhongbo; Lin, Kuang; Macklis, Jeffrey D et al. (2017) Proposed association between the hexanucleotide repeat of C9orf72 and opposability index of the thumb. Amyotroph Lateral Scler Frontotemporal Degener 18:175-181|
|Frangeul, Laura; Kehayas, Vassilis; Sanchez-Mut, Jose V et al. (2017) Input-dependent regulation of excitability controls dendritic maturation in somatosensory thalamocortical neurons. Nat Commun 8:2015|
|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|
|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|
|Shipman, Seth L; Nivala, Jeff; Macklis, Jeffrey D et al. (2016) Molecular recordings by directed CRISPR spacer acquisition. Science 353:aaf1175|
Showing the most recent 10 out of 52 publications