Polycomb-Mediated Repression and Sonic Hedgehog Signaling Interact to Regulate Merkel Cell Specification during Skin Development

被引:52
作者
Perdigoto, Carolina N. [1 ]
Dauber, Katherine L. [1 ]
Bar, Carmit [1 ]
Tsai, Pai-Chi [2 ,3 ]
Valdes, Victor J. [1 ]
Cohen, Idan [1 ]
Santoriello, Francis J. [1 ]
Zhao, Dejian
Zheng, Deyou [4 ,5 ,6 ]
Hsu, Ya-Chieh [2 ,3 ]
Ezhkova, Elena [1 ]
机构
[1] Icahn Sch Med Mt Sinai, Black Family Stem Cell Inst, Dept Dev & Regenerat Biol, New York, NY USA
[2] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA
[3] Harvard Stem Cell Inst, Cambridge, MA USA
[4] Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10467 USA
[5] Albert Einstein Coll Med, Dept Genet, Bronx, NY USA
[6] Albert Einstein Coll Med, Dept Neurosci, Bronx, NY USA
来源
PLOS GENETICS | 2016年 / 12卷 / 07期
基金
美国国家卫生研究院;
关键词
HAIR FOLLICLE MORPHOGENESIS; DERMAL PAPILLA CELLS; STEM-CELLS; BETA-CATENIN; GENE-EXPRESSION; DORSAL SKIN; EDA GENE; IN-VIVO; MOUSE; MICE;
D O I
10.1371/journal.pgen.1006151
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
An increasing amount of evidence indicates that developmental programs are tightly regulated by the complex interplay between signaling pathways, as well as transcriptional and epigenetic processes. Here, we have uncovered coordination between transcriptional and morphogen cues to specify Merkel cells, poorly understood skin cells that mediate light touch sensations. In murine dorsal skin, Merkel cells are part of touch domes, which are skin structures consisting of specialized keratinocytes, Merkel cells, and afferent neurons, and are located exclusively around primary hair follicles. We show that the developing primary hair follicle functions as a niche required for Merkel cell specification. We find that intraepidermal Sonic hedgehog (Shh) signaling, initiated by the production of Shh ligand in the developing hair follicles, is required for Merkel cell specification. The importance of Shh for Merkel cell formation is further reinforced by the fact that Shh overexpression in embryonic epidermal progenitors leads to ectopic Merkel cells. Interestingly, Shh signaling is common to primary, secondary, and tertiary hair follicles, raising the possibility that there are restrictive mechanisms that regulate Merkel cell specification exclusively around primary hair follicles. Indeed, we find that loss of Polycomb repressive complex 2 (PRC2) in the epidermis results in the formation of ectopic Merkel cells that are associated with all hair types. We show that PRC2 loss expands the field of epidermal cells competent to differentiate into Merkel cells through the upregulation of key Merkel-differentiation genes, which are known PRC2 targets. Importantly, PRC2-mediated repression of the Merkel cell differentiation program requires inductive Shh signaling to form mature Merkel cells. Our study exemplifies how the interplay between epigenetic and morphogen cues regulates the complex patterning and formation of the mammalian skin structures.
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页数:27
相关论文
共 75 条
[11]   Earlier- born secondary hair follicles exhibit phenotypic plasticity [J].
Chi, Woo ;
Wu, Eleanor ;
Morgan, Bruce A. .
EXPERIMENTAL DERMATOLOGY, 2015, 24 (04) :265-268
[12]   Dermal papilla cell number specifies hair size, shape and cycling and its reduction causes follicular decline [J].
Chi, Woo ;
Wu, Eleanor ;
Morgan, Bruce A. .
DEVELOPMENT, 2013, 140 (08) :1676-1683
[13]   Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function [J].
Chiang, C ;
Ying, LTT ;
Lee, E ;
Young, KE ;
Corden, JL ;
Westphal, H ;
Beachy, PA .
NATURE, 1996, 383 (6599) :407-413
[14]   Essential role for Sonic hedgehog during hair follicle morphogenesis [J].
Chiang, C ;
Swan, RZ ;
Grachtchouk, M ;
Bolinger, M ;
Ying, LTT ;
Robertson, EK ;
Cooper, MK ;
Gaffield, W ;
Westphal, H ;
Beachy, PA ;
Dlugosz, AA .
DEVELOPMENTAL BIOLOGY, 1999, 205 (01) :1-9
[15]   Sox2 in the Dermal Papilla Niche Controls Hair Growth by Fine-Tuning BMP Signaling in Differentiating Hair Shaft Progenitors [J].
Clavel, Carlos ;
Grisanti, Laura ;
Zemla, Roland ;
Rezza, Amelie ;
Barros, Rita ;
Sennett, Rachel ;
Mazloom, Amin Reza ;
Chung, Chi-Yeh ;
Cai, Xiaoqiang ;
Cai, Chen-Leng ;
Pevny, Larysa ;
Nicolis, Silvia ;
Ma'ayan, Avi ;
Rendl, Michael .
DEVELOPMENTAL CELL, 2012, 23 (05) :981-994
[16]  
DasGupta R, 1999, DEVELOPMENT, V126, P4557
[17]  
Dassule HR, 2000, DEVELOPMENT, V127, P4775
[18]  
Dauber KL, 2016, J INVEST DERMATOL
[19]   Clonal Growth of Dermal Papilla Cells in Hydrogels Reveals Intrinsic Differences between Sox2-Positive and -Negative Cells In Vitro and In Vivo [J].
Driskell, Ryan R. ;
Juneja, Vikram R. ;
Connelly, John T. ;
Kretzschmar, Kai ;
Tan, David W. -M. ;
Watt, Fiona M. .
JOURNAL OF INVESTIGATIVE DERMATOLOGY, 2012, 132 (04) :1084-1093
[20]   Hair follicle dermal papilla cells at a glance [J].
Driskell, Ryan R. ;
Clavel, Carlos ;
Rendl, Michael ;
Watt, Fiona M. .
JOURNAL OF CELL SCIENCE, 2011, 124 (08) :1179-1182