title: Incoherent feed-forward regulatory loops control segregation of C-mechanoreceptors, nociceptors, and pruriceptors.
abstract: Mammalian skin is innervated by diverse, unmyelinated C fibers that are associated with senses of pain, itch, temperature, or touch. A key developmental question is how this neuronal cell diversity is generated during development. We reported previously that the runt domain transcription factor Runx1 is required to coordinate the development of these unmyelinated cutaneous sensory neurons, including VGLUT3(+) low-threshold c-mechanoreceptors (CLTMs), MrgprD(+) polymodal nociceptors, MrgprA3(+) pruriceptors, MrgprB4(+) c-mechanoreceptors, and others. However, how these Runx1-dependent cutaneous sensory neurons are further segregated is poorly illustrated. Here, we find that the Runx1-dependent transcription factor gene Zfp521 is expressed in, and required for establishing molecular features that define, VGLUT3(+) CLTMs. Furthermore, Runx1 and Zfp521 form a classic incoherent feedforward loop (I-FFL) in controlling molecular identities that normally belong to MrgprD(+) neurons, with Runx1 and Zfp51 playing activator and repressor roles, respectively (in genetic terms). A knock-out of Zfp521 allows prospective VGLUT3 lineage neurons to acquire MrgprD(+) neuron identities. Furthermore, Runx1 might form other I-FFLs to regulate the expression of MrgprA3 and MrgprB4, a mechanism preventing these genes from being expressed in Runx1-persistent VGLUT3(+) and MrgprD(+) neurons. The evolvement of these I-FFLs provides an explanation for how modality-selective sensory subtypes are formed during development and may also have intriguing implications for sensory neuron evolution and sensory coding.
authors.affiliation: Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Shan
authors.identifier: http://orcid.org/0000-0002-1638-9917
authors.initials: S
authors.lastname: Lou
authors.affiliation: Zhejiang Key Laboratory of Organ Development and Regeneration, Institute of Developmental and Regenerative Biology, College of Life Sciences, Hangzhou Normal University, Hangzhou 310029, People's Republic of China.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Pan
authors.affiliation: Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Tianwen
authors.initials: T
authors.lastname: Huang
authors.affiliation: Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Bo
authors.initials: B
authors.lastname: Duan
authors.affiliation: Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and.
authors.forename: Fu-Chia
authors.initials: FC
authors.lastname: Yang
authors.affiliation: Zhejiang Key Laboratory of Organ Development and Regeneration, Institute of Developmental and Regenerative Biology, College of Life Sciences, Hangzhou Normal University, Hangzhou 310029, People's Republic of China.
authors.forename: Juan
authors.initials: J
authors.lastname: Yang
authors.affiliation: Dana-Farber Cancer Institute and.
authors.forename: Mulin
authors.initials: M
authors.lastname: Xiong
authors.affiliation: Zhejiang Key Laboratory of Organ Development and Regeneration, Institute of Developmental and Regenerative Biology, College of Life Sciences, Hangzhou Normal University, Hangzhou 310029, People's Republic of China Yang_Liu@idrbio.org Qiufu_Ma@dfci.harvard.edu.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, and Yang_Liu@idrbio.org Qiufu_Ma@dfci.harvard.edu.
authors.forename: Qiufu
authors.initials: Q
authors.lastname: Ma
mesh_terms: D026922:Amino Acid Transport Systems, Acidic / Q000502:physiology; D000818:Animals; D002452:Cell Count; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology*; D005727:Ganglia, Spinal / Q000254:growth & development / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D008465:Mechanoreceptors / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D009619:Nociceptors / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D026922:Amino Acid Transport Systems, Acidic; D050676:Core Binding Factor Alpha 2 Subunit; D043562:Receptors, G-Protein-Coupled; D014157:Transcription Factors; C472572:Evi3 protein, mouse; C546475:MrgprA3 protein, mouse; C497098:Mrgprd protein, mouse; C493726:Runx1 protein, mouse; C504941:Slc17a8 protein, mouse
keywords: Runx1; Zfp521; low-threshold c-mechanoreceptors; nociceptors; pruriceptors; sensory subtype specification
references.citation: Nat Genet. 2000 Jun;25(2):139-40
references.pmid: 10835623
references.citation: Nat Neurosci. 2015 Jan;18(1):145-53
references.pmid: 25420068
references.citation: Genome Res. 2003 Mar;13(3):476-84
references.pmid: 12618378
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):10043-8
references.pmid: 12909716
references.citation: Nature. 1983 Jan 20;301(5897):241-3
references.pmid: 6130474
references.citation: Dev Biol. 1988 Jun;127(2):316-25
references.pmid: 2837417
references.citation: Genes Dev. 1999 Jul 1;13(13):1717-28
references.pmid: 10398684
references.citation: Neuron. 2005 Jan 6;45(1):17-25
references.pmid: 15629699
references.citation: Blood. 2005 Jul 15;106(2):494-504
references.pmid: 15784726
references.citation: Neuron. 2006 Feb 2;49(3):365-77
references.pmid: 16446141
references.citation: Dev Biol. 2007 Mar 15;303(2):663-74
references.pmid: 17208218
references.citation: Nat Rev Genet. 2007 Jun;8(6):450-61
references.pmid: 17510665
references.citation: Nat Neurosci. 2007 Aug;10(8):946-8
references.pmid: 17618277
references.citation: J Neurosci. 2008 Jan 2;28(1):125-32
references.pmid: 18171930
references.citation: Nat Neurosci. 2008 Nov;11(11):1283-93
references.pmid: 18849985
references.citation: Nat Rev Neurosci. 2009 Apr;10(4):283-94
references.pmid: 19259101
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9075-80
references.pmid: 19451647
references.citation: J Neurosci. 2009 Jul 1;29(26):8612-9
references.pmid: 19571152
references.citation: Pain. 2008 Oct 31;139(3):681-7
references.pmid: 18789837
references.citation: Nature. 2009 Dec 3;462(7273):651-5
references.pmid: 19915548
references.citation: Nat Neurosci. 2010 Jan;13(1):133-40
references.pmid: 20023653
references.citation: Cell. 2009 Dec 24;139(7):1353-65
references.pmid: 20004959
references.citation: Neural Dev. 2010;5:3
references.pmid: 20096094
references.citation: Mol Pain. 2010;6:45
references.pmid: 20673362
references.citation: J Clin Invest. 2010 Nov;120(11):3773-8
references.pmid: 21041959
references.citation: Neuron. 2010 Nov 4;68(3):529-42
references.pmid: 21040852
references.citation: Neuron. 2010 Nov 4;68(3):543-56
references.pmid: 21040853
references.citation: J Cell Biol. 2010 Dec 27;191(7):1271-83
references.pmid: 21173110
references.citation: Nature. 2011 Feb 24;470(7335):503-9
references.pmid: 21326203
references.citation: Curr Opin Neurobiol. 2011 Feb;21(1):52-60
references.pmid: 20888752
references.citation: J Neurophysiol. 2011 Sep;106(3):1078-88
references.pmid: 21653727
references.citation: Dev Biol. 2011 Dec 1;360(1):77-86
references.pmid: 21945863
references.citation: Cell. 2011 Dec 23;147(7):1615-27
references.pmid: 22196735
references.citation: Dev Biol. 2012 Apr 15;364(2):114-27
references.pmid: 22326227
references.citation: Neurosci Bull. 2012 Apr;28(2):91-9
references.pmid: 22466120
references.citation: Trends Neurosci. 2012 Jun;35(6):373-81
references.pmid: 22516617
references.citation: J Neurosci. 2012 Jul 11;32(28):9706-15
references.pmid: 22787056
references.citation: J Neurosci. 2012 Oct 17;32(42):14532-7
references.pmid: 23077038
references.citation: PLoS Biol. 2012;10(11):e1001433
references.pmid: 23209378
references.citation: J Neurosci. 2013 Jan 16;33(3):870-82
references.pmid: 23325226
references.citation: Nat Neurosci. 2013 Feb;16(2):174-82
references.pmid: 23263443
references.citation: Nature. 2013 Jan 31;493(7434):669-73
references.pmid: 23364746
references.citation: Annu Rev Cell Dev Biol. 2013;29:355-84
references.pmid: 24099085
references.citation: Cell Rep. 2013 Oct 31;5(2):378-88
references.pmid: 24139797
references.citation: Cell Rep. 2013 Dec 12;5(5):1353-64
references.pmid: 24316076
references.citation: Nat Neurosci. 2014 Feb;17(2):183-91
references.pmid: 24473266
references.citation: Cell Rep. 2014 Jan 30;6(2):245-6
references.pmid: 24484769
references.citation: PLoS Genet. 2014 Feb;10(2):e1004081
references.pmid: 24516396
references.citation: J Neurosci. 2014 Sep 3;34(36):12015-28
references.pmid: 25186747
references.citation: Nat Commun. 2014;5:4984
references.pmid: 25369838
references.citation: Cell. 2001 Sep 7;106(5):619-32
references.pmid: 11551509