Publications by authors named "Pauline Marangoni"

22 Publications

  • Page 1 of 1

Parallels in signaling between development and regeneration in ectodermal organs.

Curr Top Dev Biol 2022 26;149:373-419. Epub 2022 Mar 26.

Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, United States; Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, CA, United States. Electronic address:

Ectodermal organs originate from the outermost germ layer of the developing embryo and include the skin, hair, tooth, nails, and exocrine glands. These organs develop through tightly regulated, sequential and reciprocal epithelial-mesenchymal crosstalk, and they eventually assume various morphologies and functions while retaining the ability to regenerate. As with many other tissues in the body, the development and morphogenesis of these organs are regulated by a set of common signaling pathways, such as Shh, Wnt, Bmp, Notch, Tgf-β, and Eda. However, subtle differences in the temporal activation, the multiple possible combinations of ligand-receptor activation, the various cofactors, as well as the underlying epigenetic modulation determine how each organ develops into its adult form. Although each organ has been studied separately in considerable detail, the mechanisms underlying the parallels and differences in signaling that regulate their development have rarely been investigated. First, we will use the tooth, the hair follicle, and the mammary gland as representative ectodermal organs to explore how the development of signaling centers and establishment of stem cell populations influence overall growth and morphogenesis. Then we will compare how some of the major signaling pathways (Shh, Wnt, Notch and Yap/Taz) differentially regulate developmental events. Finally, we will discuss how signaling regulates regenerative processes in all three.
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http://dx.doi.org/10.1016/bs.ctdb.2022.02.006DOI Listing
March 2022

CNPY4 inhibits the Hedgehog pathway by modulating membrane sterol lipids.

Nat Commun 2022 05 3;13(1):2407. Epub 2022 May 3.

Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, USA.

The Hedgehog (HH) pathway is critical for development and adult tissue homeostasis. Aberrant HH signaling can lead to congenital malformations and diseases including cancer. Although cholesterol and several oxysterol lipids have been shown to play crucial roles in HH activation, the molecular mechanisms governing their regulation remain unresolved. Here, we identify Canopy4 (CNPY4), a Saposin-like protein, as a regulator of the HH pathway that modulates levels of membrane sterol lipids. Cnpy4 embryos exhibit multiple defects consistent with HH signaling perturbations, most notably changes in digit number. Knockdown of Cnpy4 hyperactivates the HH pathway in vitro and elevates membrane levels of accessible sterol lipids, such as cholesterol, an endogenous ligand involved in HH activation. Our data demonstrate that CNPY4 is a negative regulator that fine-tunes HH signal transduction, revealing a previously undescribed facet of HH pathway regulation that operates through control of membrane composition.
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http://dx.doi.org/10.1038/s41467-022-30186-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065090PMC
May 2022

Dental cell type atlas reveals stem and differentiated cell types in mouse and human teeth.

Nat Commun 2020 09 23;11(1):4816. Epub 2020 Sep 23.

Department of Molecular Neuroscience, Center for Brain Research, Medical University of Vienna, Vienna, Austria.

Understanding cell types and mechanisms of dental growth is essential for reconstruction and engineering of teeth. Therefore, we investigated cellular composition of growing and non-growing mouse and human teeth. As a result, we report an unappreciated cellular complexity of the continuously-growing mouse incisor, which suggests a coherent model of cell dynamics enabling unarrested growth. This model relies on spatially-restricted stem, progenitor and differentiated populations in the epithelial and mesenchymal compartments underlying the coordinated expansion of two major branches of pulpal cells and diverse epithelial subtypes. Further comparisons of human and mouse teeth yield both parallelisms and differences in tissue heterogeneity and highlight the specifics behind growing and non-growing modes. Despite being similar at a coarse level, mouse and human teeth reveal molecular differences and species-specific cell subtypes suggesting possible evolutionary divergence. Overall, here we provide an atlas of human and mouse teeth with a focus on growth and differentiation.
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http://dx.doi.org/10.1038/s41467-020-18512-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511944PMC
September 2020

Heterogeneity within Stratified Epithelial Stem Cell Populations Maintains the Oral Mucosa in Response to Physiological Stress.

Cell Stem Cell 2019 12;25(6):814-829.e6

Department of Pathology & Laboratory Medicine, the University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, the University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address:

Stem cells in stratified epithelia are generally believed to adhere to a non-hierarchical single-progenitor model. Using lineage tracing and genetic label-retention assays, we show that the hard palatal epithelium of the oral cavity is unique in displaying marked proliferative heterogeneity. We identify a previously uncharacterized, infrequently-dividing stem cell population that resides within a candidate niche, the junctional zone (JZ). JZ stem cells tend to self-renew by planar symmetric divisions, respond to masticatory stresses, and promote wound healing, whereas frequently-dividing cells reside outside the JZ, preferentially renew through perpendicular asymmetric divisions, and are less responsive to injury. LRIG1 is enriched in the infrequently-dividing population in homeostasis, dynamically changes expression in response to tissue stresses, and promotes quiescence, whereas Igfbp5 preferentially labels a rapidly-growing, differentiation-prone population. These studies establish the oral mucosa as an important model system to study epithelial stem cell populations and how they respond to tissue stresses.
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http://dx.doi.org/10.1016/j.stem.2019.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925542PMC
December 2019

Downregulation of FGF Signaling by Overexpression Leads to Shape Impairment, Enamel Irregularities, and Delayed Signaling Center Formation in the Mouse Molar.

JBMR Plus 2019 Aug 31;3(8):e10205. Epub 2019 Jul 31.

Program in Craniofacial Biology and Department of Orofacial Sciences University of California San Francisco CA USA.

FGF signaling plays a critical role in tooth development, and mutations in modulators of this pathway produce a number of striking phenotypes. However, many aspects of the role of the FGF pathway in regulating the morphological features and the mineral quality of the dentition remain unknown. Here, we used transgenic mice overexpressing the FGF negative feedback regulator Sprouty4 under the epithelial keratin 14 promoter (K14-) to achieve downregulation of signaling in the epithelium. This led to highly penetrant defects affecting both cusp morphology and the enamel layer. We characterized the phenotype of erupted molars, identified a developmental delay in K14- transgenic embryos, and linked this with changes in the tooth developmental sequence. These data further delineate the role of FGF signaling in the development of the dentition and implicate the pathway in the regulation of tooth mineralization. © 2019 The Authors. is published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715786PMC
August 2019

A large pool of actively cycling progenitors orchestrates self-renewal and injury repair of an ectodermal appendage.

Nat Cell Biol 2019 09 2;21(9):1102-1112. Epub 2019 Sep 2.

Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, USA.

The classical model of tissue renewal posits that small numbers of quiescent stem cells (SCs) give rise to proliferating transit-amplifying cells before terminal differentiation. However, many organs house pools of SCs with proliferative and differentiation potentials that diverge from this template. Resolving SC identity and organization is therefore central to understanding tissue renewal. Here, using a combination of single-cell RNA sequencing (scRNA-seq), mouse genetics and tissue injury approaches, we uncover cellular hierarchies and mechanisms that underlie the maintenance and repair of the continuously growing mouse incisor. Our results reveal that, during homeostasis, a group of actively cycling epithelial progenitors generates enamel-producing ameloblasts and adjacent layers of non-ameloblast cells. After injury, tissue repair was achieved through transient increases in progenitor-cell proliferation and through direct conversion of Notch1-expressing cells to ameloblasts. We elucidate epithelial SC identity, position and function, providing a mechanistic basis for the homeostasis and repair of a fast-turnover ectodermal appendage.
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http://dx.doi.org/10.1038/s41556-019-0378-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935352PMC
September 2019

Sonic Hedgehog Signaling Is Required for Cyp26 Expression during Embryonic Development.

Int J Mol Sci 2019 May 8;20(9). Epub 2019 May 8.

Department of Oral Biochemistry, Sahlgrenska Academy at the University of Gothenburg, SE-40530 Göteborg, Sweden.

Deciphering how signaling pathways interact during development is necessary for understanding the etiopathogenesis of congenital malformations and disease. In several embryonic structures, components of the Hedgehog and retinoic acid pathways, two potent players in development and disease are expressed and operate in the same or adjacent tissues and cells. Yet whether and, if so, how these pathways interact during organogenesis is, to a large extent, unclear. Using genetic and experimental approaches in the mouse, we show that during development of ontogenetically different organs, including the tail, genital tubercle, and secondary palate, Sonic hedgehog (SHH) loss-of-function causes anomalies phenocopying those induced by enhanced retinoic acid signaling and that SHH is required to prevent supraphysiological activation of retinoic signaling through maintenance and reinforcement of expression of the genes. Furthermore, in other tissues and organs, disruptions of the Hedgehog or the retinoic acid pathways during development generate similar phenotypes. These findings reveal that rigidly calibrated Hedgehog and retinoic acid activities are required for normal organogenesis and tissue patterning.
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http://dx.doi.org/10.3390/ijms20092275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540044PMC
May 2019

Prominin-1 controls stem cell activation by orchestrating ciliary dynamics.

EMBO J 2019 01 6;38(2). Epub 2018 Dec 6.

Peninsula Dental School, University of Plymouth, Plymouth, UK

Proper temporal and spatial activation of stem cells relies on highly coordinated cell signaling. The primary cilium is the sensory organelle that is responsible for transmitting extracellular signals into a cell. Primary cilium size, architecture, and assembly-disassembly dynamics are under rigid cell cycle-dependent control. Using mouse incisor tooth epithelia as a model, we show that ciliary dynamics in stem cells require the proper functions of a cholesterol-binding membrane glycoprotein, Prominin-1 (Prom1/CD133), which controls sequential recruitment of ciliary membrane components, histone deacetylase, and transcription factors. Nuclear translocation of Prom1 and these molecules is particularly evident in transit amplifying cells, the immediate derivatives of stem cells. The absence of Prom1 impairs ciliary dynamics and abolishes the growth stimulation effects of sonic hedgehog (SHH) treatment, resulting in the disruption of stem cell quiescence maintenance and activation. We propose that Prom1 is a key regulator ensuring appropriate response of stem cells to extracellular signals, with important implications for development, regeneration, and diseases.
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http://dx.doi.org/10.15252/embj.201899845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331727PMC
January 2019

Bones, Glands, Ears and More: The Multiple Roles of FGF10 in Craniofacial Development.

Front Genet 2018 16;9:542. Epub 2018 Nov 16.

Program in Craniofacial Biology, Departments of Orofacial Sciences and Pediatrics, Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, United States.

Members of the fibroblast growth factor (FGF) family have myriad functions during development of both non-vertebrate and vertebrate organisms. One of these family members, , is largely expressed in mesenchymal tissues and is essential for postnatal life because of its critical role in development of the craniofacial complex, as well as in lung branching. Here, we review the function of FGF10 in morphogenesis of craniofacial organs. Genetic mouse models have demonstrated that the dysregulation or absence of FGF10 function affects the process of palate closure, and FGF10 is also required for development of salivary and lacrimal glands, the inner ear, eye lids, tongue taste papillae, teeth, and skull bones. Importantly, mutations within the locus have been described in connection with craniofacial malformations in humans. A detailed understanding of craniofacial defects caused by dysregulation of FGF10 and the precise mechanisms that underlie them offers new opportunities for development of medical treatments for patients with birth defects and for regenerative approaches for cancer patients with damaged gland tissues.
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http://dx.doi.org/10.3389/fgene.2018.00542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6250787PMC
November 2018

Quantitative Clonal Analysis and Single-Cell Transcriptomics Reveal Division Kinetics, Hierarchy, and Fate of Oral Epithelial Progenitor Cells.

Cell Stem Cell 2019 01 21;24(1):183-192.e8. Epub 2018 Nov 21.

Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, San Francisco, CA, USA; Department of Pediatrics and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, USA. Electronic address:

The oral mucosa is one of the most rapidly dividing tissues in the body and serves as a barrier to physical and chemical insults from mastication, food, and microorganisms. Breakdown of this barrier can lead to significant morbidity and potentially life-threatening infections for patients. Determining the identity and organization of oral epithelial progenitor cells (OEPCs) is therefore paramount to understanding their roles in homeostasis and disease. Using lineage tracing and label retention experiments, we show that rapidly dividing OEPCs are located broadly within the basal layer of the mucosa throughout the oral cavity. Quantitative clonal analysis demonstrated that OEPCs undergo population-asymmetrical divisions following neutral drift dynamics and that they respond to chemotherapy-induced damage by altering daughter cell fates. Finally, using single-cell RNA-seq, we establish the basal layer population structure and propose a model that defines the organization of cells within the basal layer.
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http://dx.doi.org/10.1016/j.stem.2018.10.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320295PMC
January 2019

Publisher Correction: FGF signalling controls the specification of hair placode-derived SOX9 positive progenitors to Merkel cells.

Nat Commun 2018 07 17;9(1):2854. Epub 2018 Jul 17.

Black Family Stem Cell Institute, Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA.

The originally published version of this Article contained an error in Figure 2. In panel e, the blue bar was incorrectly labelled 'KRT8(+)/TOMATO(-)'. Furthermore, during the process of preparing a correction, the publication date of the Article was inadvertently changed to June 20 2018. Both of these errors have been corrected in the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-018-05361-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050296PMC
July 2018

Publisher Correction: Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche.

Nature 2018 10;562(7727):E22

Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, USA.

In this Letter, the received date should have been 23 March 2017 instead of 13 April 2018. Authors R.M.K. and O.D.K. were incorrectly denoted as 'equally contributing' authors. The labels for 'control' and 'IFNγ' in Extended Data Fig. 4g were reversed. These have been corrected online.
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http://dx.doi.org/10.1038/s41586-018-0370-1DOI Listing
October 2018

Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche.

Nature 2018 07 27;559(7712):109-113. Epub 2018 Jun 27.

Program in Craniofacial Biology and Department of Orofacial Sciences, University of California, San Francisco, CA, USA.

Epithelial surfaces form critical barriers to the outside world and are continuously renewed by adult stem cells. Whereas dynamics of epithelial stem cells during homeostasis are increasingly well understood, how stem cells are redirected from a tissue-maintenance program to initiate repair after injury remains unclear. Here we examined infection by Heligmosomoides polygyrus, a co-evolved pathosymbiont of mice, to assess the epithelial response to disruption of the mucosal barrier. H. polygyrus disrupts tissue integrity by penetrating the duodenal mucosa, where it develops while surrounded by a multicellular granulomatous infiltrate. Crypts overlying larvae-associated granulomas did not express intestinal stem cell markers, including Lgr5, in spite of continued epithelial proliferation. Granuloma-associated Lgr5 crypt epithelium activated an interferon-gamma (IFN-γ)-dependent transcriptional program, highlighted by Sca-1 expression, and IFN-γ-producing immune cells were found in granulomas. A similar epithelial response accompanied systemic activation of immune cells, intestinal irradiation, or ablation of Lgr5 intestinal stem cells. When cultured in vitro, granuloma-associated crypt cells formed spheroids similar to those formed by fetal epithelium, and a sub-population of H. polygyrus-induced cells activated a fetal-like transcriptional program, demonstrating that adult intestinal tissues can repurpose aspects of fetal development. Therefore, re-initiation of the developmental program represents a fundamental mechanism by which the intestinal crypt can remodel itself to sustain function after injury.
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http://dx.doi.org/10.1038/s41586-018-0257-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6042247PMC
July 2018

FGF signalling controls the specification of hair placode-derived SOX9 positive progenitors to Merkel cells.

Nat Commun 2018 06 13;9(1):2333. Epub 2018 Jun 13.

Black Family Stem Cell Institute, Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, 10029, USA.

Merkel cells are innervated mechanosensory cells responsible for light-touch sensations. In murine dorsal skin, Merkel cells are located in touch domes and found in the epidermis around primary hairs. While it has been shown that Merkel cells are skin epithelial cells, the progenitor cell population that gives rise to these cells is unknown. Here, we show that during embryogenesis, SOX9-positive (+) cells inside hair follicles, which were previously known to give rise to hair follicle stem cells (HFSCs) and cells of the hair follicle lineage, can also give rise to Merkel Cells. Interestingly, while SOX9 is critical for HFSC specification, it is dispensable for Merkel cell formation. Conversely, FGFR2 is required for Merkel cell formation but is dispensable for HFSCs. Together, our studies uncover SOX9(+) cells as precursors of Merkel cells and show the requirement for FGFR2-mediated epithelial signalling in Merkel cell specification.
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http://dx.doi.org/10.1038/s41467-018-04399-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998134PMC
June 2018

Cell fate specification in the lingual epithelium is controlled by antagonistic activities of Sonic hedgehog and retinoic acid.

PLoS Genet 2017 Jul 17;13(7):e1006914. Epub 2017 Jul 17.

Department of Oral Biochemistry, Institute of Odontology, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.

The interaction between signaling pathways is a central question in the study of organogenesis. Using the developing murine tongue as a model, we uncovered unknown relationships between Sonic hedgehog (SHH) and retinoic acid (RA) signaling. Genetic loss of SHH signaling leads to enhanced RA activity subsequent to loss of SHH-dependent expression of Cyp26a1 and Cyp26c1. This causes a cell identity switch, prompting the epithelium of the tongue to form heterotopic minor salivary glands and to overproduce oversized taste buds. At developmental stages during which Wnt10b expression normally ceases and Shh becomes confined to taste bud cells, loss of SHH inputs causes the lingual epithelium to undergo an ectopic and anachronic expression of Shh and Wnt10b in the basal layer, specifying de novo taste placode induction. Surprisingly, in the absence of SHH signaling, lingual epithelial cells adopted a Merkel cell fate, but this was not caused by enhanced RA signaling. We show that RA promotes, whereas SHH, acting strictly within the lingual epithelium, inhibits taste placode and lingual gland formation by thwarting RA activity. These findings reveal key functions for SHH and RA in cell fate specification in the lingual epithelium and aid in deciphering the molecular mechanisms that assign cell identity.
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http://dx.doi.org/10.1371/journal.pgen.1006914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5536368PMC
July 2017

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

J Bone Miner Res 2017 Nov 31;32(11):2219-2231. Epub 2017 Jul 31.

Program in Craniofacial Biology and Department of Orofacial Sciences, UCSF School of Dentistry, University of California, San Francisco, San Francisco, CA, USA.

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. © 2017 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685895PMC
November 2017

Resolving stem and progenitor cells in the adult mouse incisor through gene co-expression analysis.

Elife 2017 05 5;6. Epub 2017 May 5.

Department of Orofacial Sciences and Program in Craniofacial Biology, University of California, San Francisco, San Francisco, United States.

Investigations into stem cell-fueled renewal of an organ benefit from an inventory of cell type-specific markers and a deep understanding of the cellular diversity within stem cell niches. Using the adult mouse incisor as a model for a continuously renewing organ, we performed an unbiased analysis of gene co-expression relationships to identify modules of co-expressed genes that represent differentiated cells, transit-amplifying cells, and residents of stem cell niches. Through in vivo lineage tracing, we demonstrated the power of this approach by showing that co-expression module members and define populations of incisor epithelial and mesenchymal stem cells. We further discovered that two adjacent mesenchymal tissues, the periodontium and dental pulp, are maintained by distinct pools of stem cells. These findings reveal novel mechanisms of incisor renewal and illustrate how gene co-expression analysis of intact biological systems can provide insights into the transcriptional basis of cellular identity.
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http://dx.doi.org/10.7554/eLife.24712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419740PMC
May 2017

The Interaction of Genetic Background and Mutational Effects in Regulation of Mouse Craniofacial Shape.

G3 (Bethesda) 2017 05 5;7(5):1439-1450. Epub 2017 May 5.

Alberta Children's Hospital Institute for Child and Maternal Health, University of Calgary, Alberta T2N 4N1, Canada

Inbred genetic background significantly influences the expression of phenotypes associated with known genetic perturbations and can underlie variation in disease severity between individuals with the same mutation. However, the effect of epistatic interactions on the development of complex traits, such as craniofacial morphology, is poorly understood. Here, we investigated the effect of three inbred backgrounds (129X1/SvJ, C57BL/6J, and FVB/NJ) on the expression of craniofacial dysmorphology in mice () with loss of function in three members of the Sprouty family of growth factor negative regulators (, , or ) in order to explore the impact of epistatic interactions on skull morphology. We found that the interaction of inbred background and the Sprouty genotype explains as much craniofacial shape variation as the Sprouty genotype alone. The most severely affected genotypes display a relatively short and wide skull, a rounded cranial vault, and a more highly angled inferior profile. Our results suggest that the FVB background is more resilient to Sprouty loss of function than either C57 or 129, and that loss is generally less severe than loss of or While the specific modifier genes responsible for these significant background effects remain unknown, our results highlight the value of intercrossing mice of multiple inbred backgrounds to identify the genes and developmental interactions that modulate the severity of craniofacial dysmorphology. Our quantitative results represent an important first step toward elucidating genetic interactions underlying variation in robustness to known genetic perturbations in mice.
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http://dx.doi.org/10.1534/g3.117.040659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427488PMC
May 2017

Phenotypic and evolutionary implications of modulating the ERK-MAPK cascade using the dentition as a model.

Sci Rep 2015 Jun 30;5:11658. Epub 2015 Jun 30.

Evo-Devo of Vertebrate Dentition, Institute of Functional Genomics of Lyon, ENS de Lyon, CNRS UMR 5242, Université Lyon 1 - Université de Lyon, 46 allée d'Italie, 69364 Lyon cedex 07, France.

The question of phenotypic convergence across a signalling pathway has important implications for both developmental and evolutionary biology. The ERK-MAPK cascade is known to play a central role in dental development, but the relative roles of its components remain unknown. Here we investigate the diversity of dental phenotypes in Spry2(-/-), Spry4(-/-), and Rsk2(-/Y) mice, including the incidence of extra teeth, which were lost in the mouse lineage 45 million years ago (Ma). In addition, Sprouty-specific anomalies mimic a phenotype that is absent in extant mice but present in mouse ancestors prior to 9 Ma. Although the mutant lines studied display convergent phenotypes, each gene has a specific role in tooth number determination and crown patterning. The similarities found between teeth in fossils and mutants highlight the pivotal role of the ERK-MAPK cascade during the evolution of the dentition in rodents.
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http://dx.doi.org/10.1038/srep11658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485067PMC
June 2015

RSK2 is a modulator of craniofacial development.

PLoS One 2014 8;9(1):e84343. Epub 2014 Jan 8.

Institute of Genetics and Molecular and Cellular Biology (IGBMC), Centre National de la Recherche Scientifique (UMR 7104), Institut National de la Santé et de la Recherche Médicale (U 964), University of Strasbourg, Illkirch, France ; Faculty of Dentistry, University of Strasbourg, Strasbourg France ; Reference Centre for Orodental Manifestations of Rare Diseases, Pôle de Médecine et Chirurgie Bucco-dentaires, Hôpitaux Universitaires de Strasbourg (HUS), Strasbourg, France.

Background: The RSK2 gene is responsible for Coffin-Lowry syndrome, an X-linked dominant genetic disorder causing mental retardation, skeletal growth delays, with craniofacial and digital abnormalities typically associated with this syndrome. Craniofacial and dental anomalies encountered in this rare disease have been poorly characterized.

Methodology/principal Findings: We examined, using X-Ray microtomographic analysis, the variable craniofacial dysmorphism and dental anomalies present in Rsk2 knockout mice, a model of Coffin-Lowry syndrome, as well as in triple Rsk1,2,3 knockout mutants. We report Rsk mutation produces surpernumerary teeth midline/mesial to the first molar. This highly penetrant phenotype recapitulates more ancestral tooth structures lost with evolution. Most likely this leads to a reduction of the maxillary diastema. Abnormalities of molar shape were generally restricted to the mesial part of both upper and lower first molars (M1). Expression analysis of the four Rsk genes (Rsk1, 2, 3 and 4) was performed at various stages of odontogenesis in wild-type (WT) mice. Rsk2 is expressed in the mesenchymal, neural crest-derived compartment, correlating with proliferative areas of the developing teeth. This is consistent with RSK2 functioning in cell cycle control and growth regulation, functions potentially responsible for severe dental phenotypes. To uncover molecular pathways involved in the etiology of these defects, we performed a comparative transcriptomic (DNA microarray) analysis of mandibular wild-type versus Rsk2-/Y molars. We further demonstrated a misregulation of several critical genes, using a Rsk2 shRNA knock-down strategy in molar tooth germs cultured in vitro.

Conclusions: This study reveals RSK2 regulates craniofacial development including tooth development and patterning via novel transcriptional targets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084343PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885557PMC
September 2014

Continuous dental replacement in a hyper-chisel tooth digging rodent.

Proc Natl Acad Sci U S A 2011 Oct 10;108(42):17355-9. Epub 2011 Oct 10.

Team Evo-Devo of Vertebrate Dentition, Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Unité Mixte de Recherche 5242, Centre National de la Recherche Scientifique, Ecole Normale Supérieure de Lyon, 69364 Lyon Cedex 07, France.

Contrary to their reptilian ancestors, which had numerous dental generations, mammals are known to usually develop only two generations of teeth. However, a few mammal species have acquired the ability to continuously replace their dentition by the constant addition of supernumerary teeth moving secondarily toward the front of the jaw. The resulting treadmill-like replacement is thus horizontal, and differs completely from the vertical dental succession of other mammals and their extinct relatives. Despite the developmental implications and prospects regarding the origin of supernumerary teeth, this striking innovation remains poorly documented. Here we report another case of continuous dental replacement in an African rodent, Heliophobius argenteocinereus, which combines this dental system with the progressive eruption of high-crowned teeth. The escalator-like mechanism of Heliophobius constitutes an original adaptation to hyper-chisel tooth digging involving high dental wear. Comparisons between Heliophobius and the few mammals that convergently acquired continuous dental replacement reveal that shared inherited traits, including dental mesial drift, delayed eruption, and supernumerary molars, comprise essential prerequisites to setting up this dental mechanism. Interestingly, these dental traits are present to a lesser extent in humans but are absent in mouse, the usual biological model. Consequently, Heliophobius represents a suitable model to investigate the molecular processes leading to the development of supernumerary teeth in mammals, and the accurate description of these processes could be a significant advance for further applications in humans, such as the regeneration of dental tissues.
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http://dx.doi.org/10.1073/pnas.1109615108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3198356PMC
October 2011

Regulation of tooth number by fine-tuning levels of receptor-tyrosine kinase signaling.

Development 2011 Sep;138(18):4063-73

Department of Orofacial Sciences and Program in Craniofacial and Mesenchymal Biology, University of California San Francisco, San Francisco, CA 94143, USA.

Much of our knowledge about mammalian evolution comes from examination of dental fossils, because the highly calcified enamel that covers teeth causes them to be among the best-preserved organs. As mammals entered new ecological niches, many changes in tooth number occurred, presumably as adaptations to new diets. For example, in contrast to humans, who have two incisors in each dental quadrant, rodents only have one incisor per quadrant. The rodent incisor, because of its unusual morphogenesis and remarkable stem cell-based continuous growth, presents a quandary for evolutionary biologists, as its origin in the fossil record is difficult to trace, and the genetic regulation of incisor number remains a largely open question. Here, we studied a series of mice carrying mutations in sprouty genes, the protein products of which are antagonists of receptor-tyrosine kinase signaling. In sprouty loss-of-function mutants, splitting of gene expression domains and reduced apoptosis was associated with subdivision of the incisor primordium and a multiplication of its stem cell-containing regions. Interestingly, changes in sprouty gene dosage led to a graded change in incisor number, with progressive decreases in sprouty dosage leading to increasing numbers of teeth. Moreover, the independent development of two incisors in mutants with large decreases in sprouty dosage mimicked the likely condition of rodent ancestors. Together, our findings indicate that altering genetic dosage of an antagonist can recapitulate ancestral dental characters, and that tooth number can be progressively regulated by changing levels of activity of a single signal transduction pathway.
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http://dx.doi.org/10.1242/dev.069195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3160100PMC
September 2011
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