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Transcriptional Programming of Human Mechanosensory Neuron Subtypes

73 Pages Posted: 20 Aug 2019 Sneak Peek Status: Review Complete

See all articles by Alec Nickolls

Alec Nickolls

National Institutes of Health - National Institute of Neurological Disorders and Stroke (NINDS)

MM Lee

National Institutes of Health - National Institute of Neurological Disorders and Stroke (NINDS)

DF Espinoza

National Institutes of Health - National Institute of Neurological Disorders and Stroke (NINDS)

Marcin Szczot

National Institutes of Health - National Center for Complementary and Integrative Health

R. Lam

National Institutes of Health - National Center for Complementary and Integrative Health

Q Wang

National Institutes of Health (NIH) - National Heart, Lung, and Blood Institute

Jeanette Beers

National Institutes of Health (NIH) - National Heart, Lung, and Blood Institute

Jizhong Zou

National Institutes of Health (NIH) - National Heart, Lung, and Blood Institute

MQ Nguyen

National Institutes of Health National Institute of Dental and Craniofacial Research

Hans J. Solinski

National Institutes of Health National Institute of Dental and Craniofacial Research

Mark Hoon

National Institutes of Health National Institute of Dental and Craniofacial Research

Aisha A. AlJanahi

National Institutes of Health (NIH) - National Heart, Lung, and Blood Institute

Kory R. Johnson

National Institutes of Health - National Institute of Neurological Disorders and Stroke (NINDS)

Michael E. Ward

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS)

Alexander Theodore Chesler

National Institutes of Health - National Center for Complementary and Integrative Health

Carsten G. Bönnemann

National Institutes of Health - National Institute of Neurological Disorders and Stroke (NINDS)

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Abstract

In vitro generation of human peripheral sensory neurons may provide a framework for novel drug screening platforms and disease models of touch and pain. However, derivation of a functionally pure sensory neuron population remains a major unmet challenge. We discovered that, by expressing the transcription factors NGN2 and BRN3A, human pluripotent stem cells can be induced to differentiate into a surprisingly homogenous culture of cold- and mechano-sensing neurons. Although such a neuronal subtype has not been reported in mice, we found molecular evidence of its existence in adult human sensory ganglia. Combining NGN2 and BRN3A programming with neural crest patterning, we produced two additional populations of sensory neurons, including a more specialized mechanosensory neuron subtype. Finally, we applied this system to model a rare inherited sensory disorder, characterized by profound impairment of touch sensation and proprioception, caused by inactivating mutations in PIEZO2. Together these findings establish an approach to specify distinct sensory neuron subtypes in vitro, underscoring the utility of stem cell technology to capture human-specific features of physiology and disease.

Keywords: Stem Cells, Touch, Neuronal Differentiation, PIEZO2, TRPM8, mechanosensation, Somatosensation, iPSCs

Suggested Citation

Nickolls, Alec and Lee, MM and Espinoza, DF and Szczot, Marcin and Lam, R. and Wang, Q and Beers, Jeanette and Zou, Jizhong and Nguyen, MQ and Solinski, Hans J. and Hoon, Mark and AlJanahi, Aisha A. and Johnson, Kory R. and Ward, Michael E. and Chesler, Alexander Theodore and Bönnemann, Carsten G., Transcriptional Programming of Human Mechanosensory Neuron Subtypes (August 20, 2019). NEURON-D-19-01291. Available at SSRN: https://ssrn.com/abstract=3439666 or http://dx.doi.org/10.2139/ssrn.3439666
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Alec Nickolls

National Institutes of Health - National Institute of Neurological Disorders and Stroke (NINDS) ( email )

9000 Rockville Pike
Bethesda, MD 20892
United States

MM Lee

National Institutes of Health - National Institute of Neurological Disorders and Stroke (NINDS)

9000 Rockville Pike
Bethesda, MD 20892
United States

DF Espinoza

National Institutes of Health - National Institute of Neurological Disorders and Stroke (NINDS)

9000 Rockville Pike
Bethesda, MD 20892
United States

Marcin Szczot

National Institutes of Health - National Center for Complementary and Integrative Health

United States

R. Lam

National Institutes of Health - National Center for Complementary and Integrative Health

United States

Q Wang

National Institutes of Health (NIH) - National Heart, Lung, and Blood Institute

73 Mr. Wayte Avenue
Bethesda, MD 01702
United States

Jeanette Beers

National Institutes of Health (NIH) - National Heart, Lung, and Blood Institute

73 Mr. Wayte Avenue
Bethesda, MD 01702
United States

Jizhong Zou

National Institutes of Health (NIH) - National Heart, Lung, and Blood Institute

73 Mr. Wayte Avenue
Bethesda, MD 01702
United States

MQ Nguyen

National Institutes of Health National Institute of Dental and Craniofacial Research

MD
United States

Hans J. Solinski

National Institutes of Health National Institute of Dental and Craniofacial Research

MD
United States

Mark Hoon

National Institutes of Health National Institute of Dental and Craniofacial Research ( email )

MD
United States

Aisha A. AlJanahi

National Institutes of Health (NIH) - National Heart, Lung, and Blood Institute

73 Mr. Wayte Avenue
Bethesda, MD 01702
United States

Kory R. Johnson

National Institutes of Health - National Institute of Neurological Disorders and Stroke (NINDS)

9000 Rockville Pike
Bethesda, MD 20892
United States

Michael E. Ward

National Institutes of Health (NIH) - National Institute of Neurological Disorders and Stroke (NINDS) ( email )

9000 Rockville Pike
Bethesda, MD 20892
United States

Alexander Theodore Chesler (Contact Author)

National Institutes of Health - National Center for Complementary and Integrative Health ( email )

United States

Carsten G. Bönnemann

National Institutes of Health - National Institute of Neurological Disorders and Stroke (NINDS)

9000 Rockville Pike
Bethesda, MD 20892
United States

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