ABSTRACT
During embryogenesis, ectodermal stem cells adopt different fates and form diverse ectodermal organs, such as teeth, hair follicles, mammary glands, and salivary glands. Interestingly, these ectodermal organs differ in their tissue homeostasis, which leads to differential abilities for continuous growth postnatally. Mouse molars lose the ability to grow continuously, whereas incisors retain this ability. In this study, we found that a BMP-Smad4-SHH-Gli1 signaling network may provide a niche supporting transient Sox2+ dental epithelial stem cells in mouse molars. This mechanism also plays a role in continuously growing mouse incisors. The differential fate of epithelial stem cells in mouse molars and incisors is controlled by this BMP/SHH signaling network, which partially accounts for the different postnatal growth potential of molars and incisors. Collectively, our study highlights the importance of crosstalk between two signaling pathways, BMP and SHH, in regulating the fate of epithelial stem cells during organogenesis.
Subject(s)
Bone Morphogenetic Proteins/metabolism , Hedgehog Proteins/metabolism , Incisor/growth & development , Molar/growth & development , Odontogenesis , Smad4 Protein/metabolism , Animals , Cell Proliferation , Epithelial Cells/cytology , Gene Expression Regulation, Developmental , Glycosyltransferases/biosynthesis , Incisor/embryology , Incisor/metabolism , Kruppel-Like Transcription Factors/metabolism , Mice , Molar/embryology , Molar/metabolism , Receptor, Notch1/biosynthesis , SOXB1 Transcription Factors/metabolism , Signal Transduction , Smad4 Protein/genetics , Stem Cells/cytology , Zinc Finger Protein GLI1ABSTRACT
Bone tissue undergoes constant turnover supported by stem cells. Recent studies showed that perivascular mesenchymal stem cells (MSCs) contribute to the turnover of long bones. Craniofacial bones are flat bones derived from a different embryonic origin than the long bones. The identity and regulating niche for craniofacial-bone MSCs remain unknown. Here, we identify Gli1+ cells within the suture mesenchyme as the main MSC population for craniofacial bones. They are not associated with vasculature, give rise to all craniofacial bones in the adult and are activated during injury repair. Gli1+ cells are typical MSCs in vitro. Ablation of Gli1+ cells leads to craniosynostosis and arrest of skull growth, indicating that these cells are an indispensable stem cell population. Twist1(+/-) mice with craniosynostosis show reduced Gli1+ MSCs in sutures, suggesting that craniosynostosis may result from diminished suture stem cells. Our study indicates that craniofacial sutures provide a unique niche for MSCs for craniofacial bone homeostasis and repair.
Subject(s)
Cranial Sutures/cytology , Craniosynostoses/genetics , Kruppel-Like Transcription Factors/genetics , Mesenchymal Stem Cells/cytology , Nuclear Proteins/genetics , Twist-Related Protein 1/genetics , Anilides/pharmacology , Animals , Cell Differentiation/genetics , Cranial Sutures/blood supply , Cranial Sutures/growth & development , Fracture Healing/genetics , Hedgehog Proteins/antagonists & inhibitors , Hedgehog Proteins/metabolism , Kruppel-Like Transcription Factors/metabolism , Mice , Mice, Transgenic , Osteoporosis/genetics , Pyridines/pharmacology , Receptors, G-Protein-Coupled/genetics , Smoothened Receptor , Zinc Finger Protein GLI1ABSTRACT
Growth factor signaling regulates tissue-tissue interactions to control organogenesis and tissue homeostasis. Specifically, transforming growth factor beta (TGFß) signaling plays a crucial role in the development of cranial neural crest (CNC) cell-derived bone, and loss of Tgfbr2 in CNC cells results in craniofacial skeletal malformations. Our recent studies indicate that non-canonical TGFß signaling is activated whereas canonical TGFß signaling is compromised in the absence of Tgfbr2 (in Tgfbr2(fl/fl);Wnt1-Cre mice). A haploinsufficiency of Tgfbr1 (aka Alk5) (Tgfbr2(fl/fl);Wnt1-Cre;Alk5(fl/+)) largely rescues craniofacial deformities in Tgfbr2 mutant mice by reducing ectopic non-canonical TGFß signaling. However, the relative involvement of canonical and non-canonical TGFß signaling in regulating specific craniofacial bone formation remains unclear. We compared the size and volume of CNC-derived craniofacial bones (frontal bone, premaxilla, maxilla, palatine bone, and mandible) from E18.5 control, Tgfbr2(fl/fl);Wnt1-Cre, and Tgfbr2(fl/fl);Wnt1-Cre;Alk5(fl/+)mice. By analyzing three dimensional (3D) micro-computed tomography (microCT) images, we found that different craniofacial bones were restored to different degrees in Tgfbr2(fl/fl);Wnt1-Cre;Alk5(fl/+) mice. Our study provides comprehensive information on anatomical landmarks and the size and volume of each craniofacial bone, as well as insights into the extent that canonical and non-canonical TGFß signaling cascades contribute to the formation of each CNC-derived bone. Our data will serve as an important resource for developmental biologists who are interested in craniofacial morphogenesis.
