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J Bone Miner Res. 2017 Nov;32(11):2219-2231. doi: 10.1002/jbmr.3202. Epub 2017 Jul 31.

Isl1 Controls Patterning and Mineralization of Enamel in the Continuously Renewing Mouse Incisor.

Author information

1
Program in Craniofacial Biology and Department of Orofacial Sciences, UCSF School of Dentistry, University of California, San Francisco, San Francisco, CA, USA.
2
Université Paris Descartes, Sorbonne Paris Cite, UMR S872, Paris, France.
3
Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR S872, Paris, France.
4
INSERM U872, Paris, France.
5
Department of Oral and Maxillofacial Surgery, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China.
6
Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, China.
7
Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the ASCR, v.v.i., Prague, Czech Republic.
8
Department of Pediatrics (Craniofacial Medicine), University of Washington, Seattle, WA, USA.
9
Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA.
10
Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.
11
Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA.

Abstract

Rodents are characterized by continuously renewing incisors whose growth is fueled by epithelial and mesenchymal stem cells housed in the proximal compartments of the tooth. The epithelial stem cells reside in structures known as the labial (toward the lip) and lingual (toward the tongue) cervical loops (laCL and liCL, respectively). An important feature of the rodent incisor is that enamel, the outer, highly mineralized layer, is asymmetrically distributed, because it is normally generated by the laCL but not the liCL. Here, we show that epithelial-specific deletion of the transcription factor Islet1 (Isl1) is sufficient to drive formation of ectopic enamel by the liCL stem cells, and also that it leads to production of altered enamel on the labial surface. Molecular analyses of developing and adult incisors revealed that epithelial deletion of Isl1 affected multiple, major pathways: Bmp (bone morphogenetic protein), Hh (hedgehog), Fgf (fibroblast growth factor), and Notch signaling were upregulated and associated with liCL-generated ectopic enamel; on the labial side, upregulation of Bmp and Fgf signaling, and downregulation of Shh were associated with premature enamel formation. Transcriptome profiling studies identified a suite of differentially regulated genes in developing Isl1 mutant incisors. Our studies demonstrate that ISL1 plays a central role in proper patterning of stem cell-derived enamel in the incisor and indicate that this factor is an important upstream regulator of signaling pathways during tooth development and renewal.

KEYWORDS:

AMELOGENESIS; ECTOPIC ENAMEL; ISL1; MOUSE INCISOR; TOOTH DEVELOPMENT

PMID:
28650075
PMCID:
PMC5685895
DOI:
10.1002/jbmr.3202
[Indexed for MEDLINE]
Free PMC Article

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