Publications by authors named "Ritva Rice"

23 Publications

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RAB23 coordinates early osteogenesis by repressing FGF10-pERK1/2 and GLI1.

Elife 2020 07 14;9. Epub 2020 Jul 14.

Craniofacial Development and Malformations research group, Orthodontics, Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.

Mutations in the gene encoding () cause Carpenter Syndrome, which is characterized by multiple developmental abnormalities including polysyndactyly and defects in skull morphogenesis. To understand how RAB23 regulates skull development, we generated deficient mice that survive to an age where skeletal development can be studied. Along with polysyndactyly, these mice exhibit premature fusion of multiple sutures resultant from aberrant osteoprogenitor proliferation and elevated osteogenesis in the suture. FGF10-driven FGFR1 signaling is elevated in sutures with a consequent imbalance in MAPK, Hedgehog signaling and RUNX2 expression. Inhibition of elevated pERK1/2 signaling results in the normalization of osteoprogenitor proliferation with a concomitant reduction of osteogenic gene expression, and prevention of craniosynostosis. Our results suggest a novel role for RAB23 as an upstream negative regulator of both FGFR and canonical Hh-GLI1 signaling, and additionally in the non-canonical regulation of GLI1 through pERK1/2.
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http://dx.doi.org/10.7554/eLife.55829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423339PMC
July 2020

Fibroblast growth factor 10 is a negative regulator of postnatal neurogenesis in the mouse hypothalamus.

Development 2020 07 13;147(13). Epub 2020 Jul 13.

School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK

New neurons are generated in the postnatal rodent hypothalamus, with a subset of tanycytes in the third ventricular (3V) wall serving as neural stem/progenitor cells. However, the precise stem cell niche organization, the intermediate steps and the endogenous regulators of postnatal hypothalamic neurogenesis remain elusive. Quantitative lineage-tracing revealed that conditional deletion of fibroblast growth factor 10 (Fgf10) from Fgf10-expressing β-tanycytes at postnatal days (P)4-5 results in the generation of significantly more parenchymal cells by P28, composed mostly of ventromedial and dorsomedial neurons and some glial cells, which persist into adulthood. A closer scrutiny and revealed that the 3V wall is not static and is amenable to cell movements. Furthermore, normally β-tanycytes give rise to parenchymal cells via an intermediate population of α-tanycytes with transient amplifying cell characteristics. Loss of Fgf10 temporarily attenuates the amplification of β-tanycytes but also appears to delay the exit of their α-tanycyte descendants from the germinal 3V wall. Our findings suggest that transience of cells through the α-tanycyte domain is a key feature, and Fgf10 is a negative regulator of postnatal hypothalamic neurogenesis.
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http://dx.doi.org/10.1242/dev.180950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375484PMC
July 2020

A molecular roadmap of the AGM region reveals BMPER as a novel regulator of HSC maturation.

J Exp Med 2017 Dec 1;214(12):3731-3751. Epub 2017 Nov 1.

Ontogeny of Haematopoietic Stem Cells Group, Institute for Stem Cell Research, Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, Scotland, UK

In the developing embryo, hematopoietic stem cells (HSCs) emerge from the aorta-gonad-mesonephros (AGM) region, but the molecular regulation of this process is poorly understood. Recently, the progression from E9.5 to E10.5 and polarity along the dorso-ventral axis have been identified as clear demarcations of the supportive HSC niche. To identify novel secreted regulators of HSC maturation, we performed RNA sequencing over these spatiotemporal transitions in the AGM region and supportive OP9 cell line. Screening several proteins through an ex vivo reaggregate culture system, we identify BMPER as a novel positive regulator of HSC development. We demonstrate that BMPER is associated with BMP signaling inhibition, but is transcriptionally induced by BMP4, suggesting that BMPER contributes to the precise control of BMP activity within the AGM region, enabling the maturation of HSCs within a BMP-negative environment. These findings and the availability of our transcriptional data through an accessible interface should provide insight into the maintenance and potential derivation of HSCs in culture.
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http://dx.doi.org/10.1084/jem.20162012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716029PMC
December 2017

Melanoblast development coincides with the late emerging cells from the dorsal neural tube in turtle Trachemys scripta.

Sci Rep 2017 09 21;7(1):12063. Epub 2017 Sep 21.

Developmental Biology, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.

Ectothermal reptiles have internal pigmentation, which is not seen in endothermal birds and mammals. Here we show that the development of the dorsal neural tube-derived melanoblasts in turtle Trachemys scripta is regulated by similar mechanisms as in other amniotes, but significantly later in development, during the second phase of turtle trunk neural crest emigration. The development of melanoblasts coincided with a morphological change in the dorsal neural tube between stages mature G15 and G16. The melanoblasts delaminated and gathered in the carapacial staging area above the neural tube at G16, and differentiated into pigment-forming melanocytes during in vitro culture. The Mitf-positive melanoblasts were not restricted to the dorsolateral pathway as in birds and mammals but were also present medially through the somites similarly to ectothermal anamniotes. This matched a lack of environmental barrier dorsal and lateral to neural tube and the somites that is normally formed by PNA-binding proteins that block entry to medial pathways. PNA-binding proteins may also participate in the patterning of the carapacial pigmentation as both the migratory neural crest cells and pigment localized only to PNA-free areas.
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http://dx.doi.org/10.1038/s41598-017-12352-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5608706PMC
September 2017

Mechanical constraint from growing jaw facilitates mammalian dental diversity.

Proc Natl Acad Sci U S A 2017 08 14;114(35):9403-9408. Epub 2017 Aug 14.

Developmental Biology Program, Institute of Biotechnology, University of Helsinki, FIN-00014 Helsinki, Finland;

Much of the basic information about individual organ development comes from studies using model species. Whereas conservation of gene regulatory networks across higher taxa supports generalizations made from a limited number of species, generality of mechanistic inferences remains to be tested in tissue culture systems. Here, using mammalian tooth explants cultured in isolation, we investigate self-regulation of patterning by comparing developing molars of the mouse, the model species of mammalian research, and the bank vole. A distinct patterning difference between the vole and the mouse molars is the alternate cusp offset present in the vole. Analyses of both species using 3D reconstructions of developing molars and jaws, computational modeling of cusp patterning, and tooth explants cultured with small braces show that correct cusp offset requires constraints on the lateral expansion of the developing tooth. Vole molars cultured without the braces lose their cusp offset, and mouse molars cultured with the braces develop a cusp offset. Our results suggest that cusp offset, which changes frequently in mammalian evolution, is more dependent on the 3D support of the developing jaw than other aspects of tooth shape. This jaw-tooth integration of a specific aspect of the tooth phenotype indicates that organs may outsource specific aspects of their morphology to be regulated by adjacent body parts or organs. Comparative studies of morphologically different species are needed to infer the principles of organogenesis.
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http://dx.doi.org/10.1073/pnas.1707410114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584446PMC
August 2017

Development of the turtle plastron, the order-defining skeletal structure.

Proc Natl Acad Sci U S A 2016 May 25;113(19):5317-22. Epub 2016 Apr 25.

Developmental Biology, Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland; Department of Biology, Swarthmore College, Swarthmore, PA 19081;

The dorsal and ventral aspects of the turtle shell, the carapace and the plastron, are developmentally different entities. The carapace contains axial endochondral skeletal elements and exoskeletal dermal bones. The exoskeletal plastron is found in all extant and extinct species of crown turtles found to date and is synaptomorphic of the order Testudines. However, paleontological reconstructed transition forms lack a fully developed carapace and show a progression of bony elements ancestral to the plastron. To understand the evolutionary development of the plastron, it is essential to know how it has formed. Here we studied the molecular development and patterning of plastron bones in a cryptodire turtle Trachemys scripta We show that plastron development begins at developmental stage 15 when osteochondrogenic mesenchyme forms condensates for each plastron bone at the lateral edges of the ventral mesenchyme. These condensations commit to an osteogenic identity and suppress chondrogenesis. Their development overlaps with that of sternal cartilage development in chicks and mice. Thus, we suggest that in turtles, the sternal morphogenesis is prevented in the ventral mesenchyme by the concomitant induction of osteogenesis and the suppression of chondrogenesis. The osteogenic subroutines later direct the growth and patterning of plastron bones in an autonomous manner. The initiation of plastron bone development coincides with that of carapacial ridge formation, suggesting that the development of dorsal and ventral shells are coordinated from the start and that adopting an osteogenesis-inducing and chondrogenesis-suppressing cell fate in the ventral mesenchyme has permitted turtles to develop their order-specific ventral morphology.
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http://dx.doi.org/10.1073/pnas.1600958113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868452PMC
May 2016

Emerging from the rib: resolving the turtle controversies.

J Exp Zool B Mol Dev Evol 2015 May 11;324(3):208-20. Epub 2015 Feb 11.

Institute of Biotechnology, University of Helsinki, Helsinki, Finland.

Two of the major controversies in the present study of turtle shell development involve the mechanism by which the carapacial ridge initiates shell formation and the mechanism by which each rib forms the costal bones adjacent to it. This paper claims that both sides of each debate might be correct-but within the species examined. Mechanism is more properly "mechanisms," and there is more than one single way to initiate carapace formation and to form the costal bones. In the initiation of the shell, the rib precursors may be kept dorsal by either "axial displacement" (in the hard-shell turtles) or "axial arrest" (in the soft-shell turtle Pelodiscus), or by a combination of these. The former process would deflect the rib into the dorsal dermis and allow it to continue its growth there, while the latter process would truncate rib growth. In both instances, though, the result is to keep the ribs from extending into the ventral body wall. Our recent work has shown that the properties of the carapacial ridge, a key evolutionary innovation of turtles, differ greatly between these two groups. Similarly, the mechanism of costal bone formation may differ between soft-shell and hard-shell turtles, in that the hard-shell species may have both periosteal flattening as well as dermal bone induction, while the soft-shelled turtles may have only the first of these processes.
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http://dx.doi.org/10.1002/jez.b.22600DOI Listing
May 2015

Late-emigrating trunk neural crest cells in turtle embryos generate an osteogenic ectomesenchyme in the plastron.

Dev Dyn 2013 Nov 6;242(11):1223-35. Epub 2013 Sep 6.

Biology Department, Millersville University, Millersville, Pennsylvania.

Background: The turtle plastron is composed of a keratinized epidermis overlying nine dermal bones. Its developmental origin has been controversial; recent evidence suggests that the plastral bones derive from trunk neural crest cells (NCCs).

Results: This study extends the observations that there is a turtle-specific, second wave of trunk NCC delamination and migration, after the original NCCs have reached their destination and differentiated. This second wave was confirmed by immunohistochemistry in whole-mounts and serial sections, by injecting DiI (1,1', di-octadecyl-3,3,3',3',-tetramethylindo-carbocyanine perchlorate) into the lumen of the neural tube and tracing labeled cells into the plastron, and by isolating neural tubes from older turtle embryos and observing delaminating NCCs. This later migration gives rise to a plastral ectomesenchyme that expresses NCC markers and can be induced to initiate bone formation.

Conclusions: The NCCs of this second migration have properties similar to those of the earlier NCCs, but also express markers characteristic of cranial NCCs. The majority of the cells of the plastron mesenchyme express neural crest markers, and have osteogenic differentiation capabilities that are similar or identical to craniofacial ectomesenchyme. Our evidence supports the contention that turtle plastron bones are derived from a late emigrating population of cells derived from the trunk neural crest.
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http://dx.doi.org/10.1002/dvdy.24018DOI Listing
November 2013

Fgf10-expressing tanycytes add new neurons to the appetite/energy-balance regulating centers of the postnatal and adult hypothalamus.

J Neurosci 2013 Apr;33(14):6170-80

School of Biological Sciences, University of East Anglia, Norwich, NR4 7TJ, United Kingdom.

Increasing evidence suggests that neurogenesis occurs in the postnatal and adult mammalian hypothalamus. However, the identity and location of the putative progenitor cells is under much debate, and little is known about the dynamics of neurogenesis in unchallenged brain. Previously, we postulated that Fibroblast growth factor 10-expressing (Fgf10(+)) tanycytes constitute a population of progenitor cells in the mouse hypothalamus. Here, we show that Fgf10(+) tanycytes express markers of neural stem/progenitor cells, divide late into postnatal life, and can generate both neurons and astrocytes in vivo. Stage-specific lineage-tracing of Fgf10(+) tanycytes using Fgf10-creERT2 mice, reveals robust neurogenesis at postnatal day 28 (P28), lasting as late as P60. Furthermore, we present evidence for amplification of Fgf10-lineage traced neural cells within the hypothalamic parenchyma itself. The neuronal descendants of Fgf10(+) tanycytes predominantly populate the arcuate nucleus, a subset of which express the orexigenic neuronal marker, Neuropeptide-Y, and respond to fasting and leptin-induced signaling. These studies provide direct evidence in support of hypothalamic neurogenesis during late postnatal and adult life, and identify Fgf10(+) tanycytes as a source of parenchymal neurons with putative roles in appetite and energy balance.
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http://dx.doi.org/10.1523/JNEUROSCI.2437-12.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3736310PMC
April 2013

Noggin null allele mice exhibit a microform of holoprosencephaly.

Hum Mol Genet 2011 Oct 5;20(20):4005-15. Epub 2011 Aug 5.

Department of Craniofacial Development, King's College, London, UK.

Holoprosencephaly (HPE) is a heterogeneous craniofacial and neural developmental anomaly characterized in its most severe form by the failure of the forebrain to divide. In humans, HPE is associated with disruption of Sonic hedgehog and Nodal signaling pathways, but the role of other signaling pathways has not yet been determined. In this study, we analyzed mice which, due to the lack of the Bmp antagonist Noggin, exhibit elevated Bmp signaling. Noggin(-/-) mice exhibited a solitary median maxillary incisor that developed from a single dental placode, early midfacial narrowing as well as abnormalities in the developing hyoid bone, pituitary gland and vomeronasal organ. In Noggin(-/-) mice, the expression domains of Shh, as well as the Shh target genes Ptch1 and Gli1, were reduced in the frontonasal region at key stages of early facial development. Using E10.5 facial cultures, we show that excessive BMP4 results in reduced Fgf8 and Ptch1 expression. These data suggest that increased Bmp signaling in Noggin(-/-) mice results in downregulation of the hedgehog pathway at a critical stage when the midline craniofacial structures are developing, which leads to a phenotype consistent with a microform of HPE.
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http://dx.doi.org/10.1093/hmg/ddr329DOI Listing
October 2011

Gli3Xt-J/Xt-J mice exhibit lambdoid suture craniosynostosis which results from altered osteoprogenitor proliferation and differentiation.

Hum Mol Genet 2010 Sep 22;19(17):3457-67. Epub 2010 Jun 22.

Department of Orthodontics, Institute of Dentistry, 00014 University of Helsinki, PO Box 41 (Mannerheimintie 172), Finland.

Gli3 is a zinc-finger transcription factor whose activity is dependent on the level of hedgehog (Hh) ligand. Hh signaling has key roles during endochondral ossification; however, its role in intramembranous ossification is still unclear. In this study, we show that Gli3 performs a dual role in regulating both osteoprogenitor proliferation and osteoblast differentiation during intramembranous ossification. We discovered that Gli3Xt-J/Xt-J mice, which represent a Gli3-null allele, exhibit craniosynostosis of the lambdoid sutures and that this is accompanied by increased osteoprogenitor proliferation and differentiation. These cellular changes are preceded by ectopic expression of the Hh receptor Patched1 and reduced expression of the transcription factor Twist1 in the sutural mesenchyme. Twist1 is known to delay osteogenesis by binding to and inhibiting the transcription factor Runx2. We found that Runx2 expression in the lambdoid suture was altered in a pattern complimentary to that of Twist1. We therefore propose that loss of Gli3 results in a Twist1-, Runx2-dependent expansion of the sutural osteoprogenitor population as well as enhanced osteoblastic differentiation which results in a bony bridge forming between the parietal and interparietal bones. We show that FGF2 will induce Twist1, normalize osteoprogenitor proliferation and differentiation and rescue the lambdoid suture synostosis in Gli3Xt-J/Xt-J mice. Taken together, we define a novel role for Gli3 in osteoblast development; we describe the first mouse model of lambdoid suture craniosynostosis and show how craniosynostosis can be rescued in this model.
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http://dx.doi.org/10.1093/hmg/ddq258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916710PMC
September 2010

Locate, condense, differentiate, grow and confront: developmental mechanisms controlling intramembranous bone and suture formation and function.

Front Oral Biol 2008 ;12:22-40

Departments of Orthodontics and Craniofacial Development, King's College London, London, UK; Department of Orthodontics, University of Helsinki, Helsinki, Finland.

The key mechanisms controlling where and when craniofacial bones and hence sutures form are discussed in this review. These include the formation and growth of skeletogenic condensations, tissue to tissue interactions between the epithelium, skeletogenic mesenchyme and the underlying dural and neural tissues. Also discussed are the key processes determining intramembranous bone growth, namely osteoblastogenesis and osteoclastogenesis.
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http://dx.doi.org/10.1159/000115030DOI Listing
June 2008

Cell fate specification during calvarial bone and suture development.

Dev Biol 2007 Nov 14;311(2):335-46. Epub 2007 Sep 14.

Departments of Craniofacial Development and Orthodontics, Floor 27 Guy's Tower, King's College, London, SE1 9RT, UK.

In this study we have addressed the fundamental question of what cellular mechanisms control the growth of the calvarial bones and conversely, what is the fate of the sutural mesenchymal cells when calvarial bones approximate to form a suture. There is evidence that the size of the osteoprogenitor cell population determines the rate of calvarial bone growth. In calvarial cultures we reduced osteoprogenitor cell proliferation; however, we did not observe a reduction in the growth of parietal bone to the same degree. This discrepancy prompted us to study whether suture mesenchymal cells participate in the growth of the parietal bones. We found that mesenchymal cells adjacent to the osteogenic fronts of the parietal bones could differentiate towards the osteoblastic lineage and could become incorporated into the growing bone. Conversely, mid-suture mesenchymal cells did not become incorporated into the bone and remained undifferentiated. Thus mesenchymal cells have different fate depending on their position within the suture. In this study we show that continued proliferation of osteoprogenitors in the osteogenic fronts is the main mechanism for calvarial bone growth, but importantly, we show that suture mesenchyme cells can contribute to calvarial bone growth. These findings help us understand the mechanisms of intramembranous ossification in general, which occurs not only during cranial and facial bone development but also in the surface periosteum of most bones during modeling and remodeling.
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http://dx.doi.org/10.1016/j.ydbio.2007.08.028DOI Listing
November 2007

Gli3-mediated somitic Fgf10 expression gradients are required for the induction and patterning of mammary epithelium along the embryonic axes.

Development 2006 Jun;133(12):2325-35

The Saban Research Institute of Childrens Hospital Los Angeles/University of Southern California, Developmental Biology Program, Los Angeles, CA 90027, USA.

Little is known about the regulation of cell fate decisions that lead to the formation of five pairs of mammary placodes in the surface ectoderm of the mouse embryo. We have previously shown that fibroblast growth factor 10 (FGF10) is required for the formation of mammary placodes 1, 2, 3 and 5. Here, we have found that Fgf10 is expressed only in the somites underlying placodes 2 and 3, in gradients across and within these somites. To test whether somitic FGF10 is required for the formation of these two placodes, we analyzed a number of mutants with different perturbations of somitic Fgf10 gradients for the presence of WNT signals and ectodermal multilayering, markers for mammary line and placode formation. The mammary line is displaced dorsally, and formation of placode 3 is impaired in Pax3ILZ/ILZ mutants, which do not form ventral somitic buds. Mammary line formation is impaired and placode 3 is absent in Gli3Xt-J/Xt-J and hypomorphic Fgf10 mutants, in which the somitic Fgf10 gradient is shortened dorsally and less overall Fgf10 is expressed, respectively. Recombinant FGF10 rescued mammogenesis in Fgf10(-/-) and Gli3Xt-J/Xt-J flanks. We correlate increasing levels of somitic FGF10 with progressive maturation of the surface ectoderm, and show that full expression of somitic Fgf10, co-regulated by GLI3, is required for the anteroposterior pattern in which the flank ectoderm acquires a mammary epithelial identity. We propose that the intra-somitic Fgf10 gradient, together with ventral elongation of the somites, determines the correct dorsoventral position of mammary epithelium along the flank.
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http://dx.doi.org/10.1242/dev.02394DOI Listing
June 2006

Expression patterns of Hedgehog signalling pathway members during mouse palate development.

Gene Expr Patterns 2006 Jan 15;6(2):206-12. Epub 2005 Sep 15.

Department of Craniofacial Development, King's College London, Floor 28 Guy's Tower, St Thomas Street, London SE1 9RT, UK.

Hedgehog signalling regulates morphogenesis of many developing organs. Sonic hedgehog (Shh) signalling has been shown to regulate the growth and morphogenesis of the palatal shelves prior to their elevation and fusion. Here, we show that Shh expression is limited to a thickened palatal oral epithelium prior to palatal shelf elevation. After palatal shelf elevation above the tongue, Shh is expressed only in small areas of thickened palatal oral epithelium that corresponded to developing rugae. The receptor Ptc1 and a regulator of Hh signalling Hhip1 are expressed in the mesenchyme adjacent to the palatal oral epithelium so that the highest level of transcripts localize to the palatal mesenchyme surrounding the Shh-expressing thickened epithelium. Smoothened and transcriptional effectors Gli1-3, and Hh regulator Gas1 are expressed widely in the palatal mesenchyme. No differences were found in the expression patterns of Hh pathway members along the anterior-posterior axis of the developing palate.
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http://dx.doi.org/10.1016/j.modgep.2005.06.005DOI Listing
January 2006

Regulation of Twist, Snail, and Id1 is conserved between the developing murine palate and tooth.

Dev Dyn 2005 Sep;234(1):28-35

Department of Craniofacial Development, King's College London, UK.

The development of both the tooth and palate requires coordinated bone morphogenetic protein (BMP) and fibroblast growth factor (FGF) signalling between epithelial and mesenchymal tissues. Here, we demonstrate that transcription factors Twist and Snail are downstream targets of FGF signalling, that Id1 and Msx2 are downstream targets of BMP signalling, and that Msx1 is regulated by both signalling pathways during tooth and palate development. We show that Twist and Snail expression in the mesenchyme is regulated by the overlying epithelium and that exogenous FGF4 in tooth and FGF2 in palate can mimic this regulation in isolated mesenchymal explants. Ids act in a dominant-negative manner to inhibit the function of other transcription factors such as Twist and Snail. FGF and BMP signalling can regulate development antagonistically, and we suggest that FGF-regulated Twist and Snail and BMP-regulated Id1 may mediate these antagonistic effects during both tooth and palate development.
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http://dx.doi.org/10.1002/dvdy.20501DOI Listing
September 2005

Foxc1 integrates Fgf and Bmp signalling independently of twist or noggin during calvarial bone development.

Dev Dyn 2005 Jul;233(3):847-52

Developmental Biology Programme, Institute of Biotechnology, University of Helsinki, Finland.

Calvarial bone and suture development is under complex regulation where bone morphogenetic protein (Bmp) and fibroblast growth factor (Fgf) signalling interact with Msx2/Twist and Noggin and regulate frontal bone primordia proliferation and suture fusion, respectively. We have shown previously that the winged helix transcription factor Foxc1, which is necessary for calvarial bone development, is required for the Bmp regulation of Msx2. We now show that FGF2 regulates the expression of Foxc1, indicating that Foxc1 integrates Bmp and Fgf signalling pathways. We also show that Foxc1 is not needed for the acquisition of osteogenic potential or for the differentiation of osteoblasts. The expression of Fgf receptors and Twist were normal in Foxc1-deficient calvarial mesenchyme, and ectopic FGF2 was able to induce the expression Osteopontin. Furthermore, we demonstrate that Foxc1 does not participate in the regulation of Noggin expression. Our findings indicate that Foxc1 integrates the Bmp and Fgf signalling pathways independently of Twist or Noggin. This signalling network is essential for the correct patterning and growth of calvarial bones.
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http://dx.doi.org/10.1002/dvdy.20430DOI Listing
July 2005

Chondrogenic potential of mouse calvarial mesenchyme.

J Histochem Cytochem 2005 May;53(5):653-63

Developmental Biology Programme, Institute of Biotechnology, PO Box 56, FIN-00014, University of Helsinki, Finland.

Facial and calvarial bones form intramembranously without a cartilagenous model; however, cultured chick calvarial mesenchyme cells may differentiate into both osteoblasts and chondroblasts and, in rodents, small cartilages occasionally form at the sutures in vivo. Therefore, we wanted to investigate what factors regulate normal differentiation of calvarial mesenchymal cells directly into osteoblasts. In embryonic mouse heads and in cultured tissue explants, we analyzed the expression of selected transcription factors and extracellular matrix molecules associated with bone and cartilage development. Cartilage markers Sox9 and type II collagen were expressed in all craniofacial cartilages. In addition, Msx2 and type I collagen were expressed in sense capsule cartilages. We also observed that the undifferentiated calvarial mesenchyme and the osteogenic fronts in the jaw expressed Col2A1. Moreover, we found that cultured mouse calvarial mesenchyme could develop into cartilage. Of the 49 explants that contained mesenchyme, intramembranous ossification occurred in 35%. Only cartilage formed in 4%, and both cartilage and bone formed in 4%. Our study confirms that calvarial mesenchyme, which normally gives rise to intramembranous bone, also has chondrogenic potential.
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http://dx.doi.org/10.1369/jhc.4A6518.2005DOI Listing
May 2005

Delineation of mechanisms and regions of dosage imbalance in complex rearrangements of 1p36 leads to a putative gene for regulation of cranial suture closure.

Eur J Hum Genet 2005 Feb;13(2):139-49

Health Research and Education Center, Washington State University, Spokane, WA 99210, USA.

Structural chromosome abnormalities have aided in gene identification for over three decades. Delineation of the deletion sizes and rearrangements allows for phenotype/genotype correlations and ultimately assists in gene identification. In this report, we have delineated the precise rearrangements in four subjects with deletions, duplications, and/or triplications of 1p36 and compared the regions of imbalance to two cases recently published. Fluorescence in situ hybridization (FISH) analysis revealed the size, order, and orientation of the duplicated/triplicated segments in each subject. We propose a premeiotic model for the formation of these complex rearrangements in the four newly ascertained subjects, whereby a deleted chromosome 1 undergoes a combination of multiple breakage-fusion-bridge (BFB) cycles and inversions to produce a chromosome arm with a complex rearrangement of deleted, duplicated and triplicated segments. In addition, comparing the six subjects' rearrangements revealed a region of overlap that when triplicated is associated with craniosynostosis and when deleted is associated with large, late-closing anterior fontanels. Within this region are the MMP23A and -B genes. We show MMP23 gene expression at the cranial sutures and we propose that haploinsufficiency results in large, late-closing anterior fontanels and overexpression results in craniosynostosis. These data emphasize the important role of cytogenetics in investigating and uncovering the etiologies of human genetic disease, particularly cytogenetic imbalances that reveal potentially dosage-sensitive genes.
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http://dx.doi.org/10.1038/sj.ejhg.5201302DOI Listing
February 2005

Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate.

J Clin Invest 2004 Jun;113(12):1692-700

Departments of Craniofacial Development and Orthodontics, King's College, London, United Kingdom.

Classical research has suggested that early palate formation develops via epithelial-mesenchymal interactions, and in this study we reveal which signals control this process. Using Fgf10-/-, FGF receptor 2b-/- (Fgfr2b-/-), and Sonic hedgehog (Shh) mutant mice, which all exhibit cleft palate, we show that Shh is a downstream target of Fgf10/Fgfr2b signaling. Our results demonstrate that mesenchymal Fgf10 regulates the epithelial expression of Shh, which in turn signals back to the mesenchyme. This was confirmed by demonstrating that cell proliferation is decreased not only in the palatal epithelium but also in the mesenchyme of Fgfr2b-/- mice. These results reveal a new role for Fgf signaling in mammalian palate development. We show that coordinated epithelial-mesenchymal interactions are essential during the initial stages of palate development and require an Fgf-Shh signaling network.
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http://dx.doi.org/10.1172/JCI20384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC420504PMC
June 2004

Runx2 mediates FGF signaling from epithelium to mesenchyme during tooth morphogenesis.

Dev Biol 2004 Jun;270(1):76-93

Institute of Biotechnology, Viikki Biocenter, University of Helsinki, 00014 Helsinki, Finland.

Runx2 (Cbfa1) is a runt domain transcription factor that is essential for bone development and tooth morphogenesis. Teeth form as ectodermal appendages and their development is regulated by interactions between the epithelium and mesenchyme. We have shown previously that Runx2 is expressed in the dental mesenchyme and regulated by FGF signals from the epithelium, and that tooth development arrests at late bud stage in Runx2 knockout mice [Development 126 (1999) 2911]. In the present study, we have continued to clarify the role of Runx2 in tooth development and searched for downstream targets of Runx2 by extensive in situ hybridization analysis. The expression of Fgf3 was downregulated in the mesenchyme of Runx2 mutant teeth. FGF-soaked beads failed to induce Fgf3 expression in Runx2 mutant dental mesenchyme whereas in wild-type mesenchyme they induced Fgf3 in all explants indicating a requirement of Runx2 for transduction of FGF signals. Fgf3 was absent also in cultured Runx2-/- calvarial cells and it was induced by overexpression of Runx2. Furthermore, Runx2 was downregulated in Msx1 mutant tooth germs, indicating that it functions in the dental mesenchyme between Msx1 and Fgf3. Shh expression was absent from the epithelial enamel knot in lower molars of Runx2 mutant and reduced in upper molars. However, other enamel knot marker genes were expressed normally in mutant upper molars, while reduced or missing in lower molars. These differences between mutant upper and lower molars may be explained by the substitution of Runx2 function by Runx3, another member of the runt gene family that was upregulated in upper but not lower molars of Runx2 mutants. Shh expression in mutant enamel knots was not rescued by FGFs in vitro, indicating that in addition to Fgf3, Runx2 regulates other mesenchymal genes required for early tooth morphogenesis. Also, exogenous FGF and SHH did not rescue the morphogenesis of Runx2 mutant molars. We conclude that Runx2 mediates the functions of epithelial FGF signals regulating Fgf3 expression in the dental mesenchyme and that Fgf3 may be a direct target gene of Runx2.
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http://dx.doi.org/10.1016/j.ydbio.2004.02.012DOI Listing
June 2004

Progression of calvarial bone development requires Foxc1 regulation of Msx2 and Alx4.

Dev Biol 2003 Oct;262(1):75-87

Developmental Biology Programme, Institute of Biotechnology, P.O. Box 56, 00014 University of Helsinki, Finland.

Calvarial bones form by direct ossification of mesenchyme. This requires condensation of mesenchymal cells which then proliferate and differentiate into osteoblasts. Congenital hydrocephalus (ch) mutant mice lack the forkhead/winged helix transcription factor Foxc1. In ch mutant mice, calvarial bones remain rudimentary at the sites of initial osteogenic condensations. In this study, we have localized the ossification defect in ch mutants to the calvarial mesenchyme, which lacks the expression of transcription factors Msx2 and Alx4. This lack of expression is associated with a reduction in the proliferation of osteoprogenitor cells. We have previously shown that BMP induces Msx2 in calvarial mesenchyme (Development 125, 1241-1251, 1998). Here, we show that BMP also induces Alx4 in this tissue. We also show that BMP-induced expression of Msx2 and Alx4 requires Foxc1. We therefore suggest that Foxc1 regulates BMP-mediated osteoprogenitor proliferation and that this regulation is required for the progression of osteogenesis beyond the initial condensations in calvarial bone development.
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http://dx.doi.org/10.1016/s0012-1606(03)00355-5DOI Listing
October 2003

Molecular mechanisms in calvarial bone and suture development, and their relation to craniosynostosis.

Eur J Orthod 2003 Apr;25(2):139-48

Developmental Biology Programme, Institute of Biotechnology, and Department of Pedodontics and Orthodontics, Institute of Dentistry, University of Helsinki, Finland.

The development and growth of the skull is a co-ordinated process involving many different tissues that interact with each other to form a complex end result. When normal development is disrupted, debilitating pathological conditions, such as craniosynostosis (premature calvarial suture fusion) and cleidocranial dysplasia (delayed suture closure), can result. It is known that mutations in the fibroblast growth factor receptors 1, 2, and 3(FGFR1, 2, and 3), as well as the transcription factors MSX2 and TWIST cause craniosynostosis, and that mutations in the transcription factor RUNX2 (CBFA1) cause cleidocranial dysplasia. However, relatively little is known about the development of the calvaria: where and when these genes are active during normal calvarial development, how these genes may interact in the developing calvaria, and the disturbances that may occur to cause these disorders. In this work an attempt has been made to address some of these questions from a basic biological perspective. The expression patterns of the above-mentioned genes in the developing mouse skull are detailed. The microdissection and in vitro culture techniques have begun the task of identifying Fgfrs, Msx2, and Twist interacting in intricate signalling pathways that if disrupted could lead to craniosynostosis.
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http://dx.doi.org/10.1093/ejo/25.2.139DOI Listing
April 2003