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

Abstract

Summary 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, as 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 up-regulated and associated with liCL-generated ectopic enamel; on the labial side, up-regulation of Bmp and Fgf signaling, and Shh down-regulation, 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.

The Role of Fibroblast Growth Factors in Tooth Development and Incisor Renewal

“…The mesenchymal expression of Fgf is partially activated via transcription factors MSX1 and PAX9, which can initiate Fgf3 and Fgf10 by E12.5 and in turn contribute to subsequent incisor development [ 128 , 139 , 140 ]. Moreover, with epithelial deletion of Isl1 , FGF signaling is upregulated and is associated with both lingual cervical loop-generated ectopic enamel and labial side premature enamel formation [ 141 ]. FGF signaling and downstream signal transduction pathways are also suppressed in Ring1a −/− ;Ring1b cko/cko incisors [ 142 ].…”

Genome-wide Analyses Identify a Novel Risk Locus for Nonsyndromic Cleft Palate

“…3). Among members of the Islet family, ISL1 is involved in the development of multiple tissues, including outgrowth of the lower jaw, as well as the patterning and mineralization of enamel (Li, Fu, et al 2017; Naveau et al 2017). The high sequence conservation between ISL1 and ISL2 suggests ISL2 might have a similar biological function.…”

Rathke’s cleft-like cysts arise from Isl1 deletion in murine pituitary progenitors

“…Thus, ISL1 is necessary to suppress alternate cell fates in pituitary progenitors. ISL1 represses alternate cell fates in neuronal and tooth development, although the mechanism in those tissues is unknown (87,88).…”