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J Neurosci. 2017 May 31;37(22):5549-5561. doi: 10.1523/JNEUROSCI.0094-17.2017. Epub 2017 May 5.

Hierarchical Specification of Pruriceptors by Runt-Domain Transcription Factor Runx1.

Qi L1,2, Huang C3, Wu X1, Tao Y1, Yan J1, Shi T1, Cao C3, Han L1, Qiu M1,2, Ma Q4,5, Liu Z6, Liu Y7.

Author information

1
Zhejiang Key Laboratory of Organ Development and Regeneration, Institute of Life Sciences, Hangzhou Normal University, Hangzhou 310036, People's Republic of China.
2
College of Life Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.
3
Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China.
4
Dana-Farber Cancer Institute and.
5
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and.
6
Beijing Institute of Biotechnology, Beijing 100850, People's Republic of China, zijingsy@yahoo.com Yang_Liu@idrbio.org.
7
Zhejiang Key Laboratory of Organ Development and Regeneration, Institute of Life Sciences, Hangzhou Normal University, Hangzhou 310036, People's Republic of China, zijingsy@yahoo.com Yang_Liu@idrbio.org.

Abstract

The somatic sensory neurons in dorsal root ganglia (DRG) detect and transmit a diverse array of sensory modalities, such as pain, itch, cold, warm, touch, and others. Recent genetic and single-cell RNA sequencing studies have revealed a group of DRG neurons that could be particularly relevant for acute and chronic itch information transmission. They express the natriuretic peptide type B (NPPB), as well as a cohort of receptors and neuropeptides that have been implicated in chronic itch manifestation, including the interleukin-31 receptor A (IL-31ra) and its coreceptor oncostatin M receptor (Osmr), the cysteinyl leukotriene receptor 2 (Cysltr2), somatostatin, and neurotensin. However, how these neurons are generated during development remains unclear. Here we report that Runx1 is required to establish all these molecular features of NPPB+ neurons. We further show that while early embryonic Runx1 activity is required for the formation of NPPB+ cells, at later stages Runx1 switches to a genetic repressor and thus its downregulation becomes a prerequisite for the proper development of these pruriceptors. This mode by Runx1 is analogous to that in controlling another group of pruriceptors that specifically express the chloroquine receptor MrgprA3. Finally, behavioral studies using both sexes of mice revealed marked deficits in processing acute and chronic itch in Runx1 conditional knock-out mice, possibly attributable to impaired development of various pruriceptors.SIGNIFICANCE STATEMENT Our studies reveal a generalized control mode by Runx1 for pruriceptor development and consolidate a hierarchical control mechanism for the formation of sensory neurons transmitting distinct modalities. Among dorsal root ganglion neurons that initially express the neurotrophin receptor TrkA, Runx1 is necessary for the proper development of those neurons that innervate tissues derived from the ectoderm such as skin epidermis and hair follicles. These Runx1-dependent cutaneous sensory neurons are then divided into two groups based on persistent or transient Runx1 expression. The Runx1-persistent group is involved in transmitting mechanical and thermal information, whereas the Runx1-transient group transmits pruriceptive information. Such hierarchical control mechanisms may provide a developmental solution for the formation of sensory circuits that transmit distinct modalities.

KEYWORDS:

NPPB; Runx1; chronic itch; development; pruriceptor; transcriptional regulation

PMID:
28476948
PMCID:
PMC6596529
DOI:
10.1523/JNEUROSCI.0094-17.2017
[Indexed for MEDLINE]
Free PMC Article

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