Joy Marion Richman
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The role of non-canonical WNT signaling in facial and limb development in the chicken embryo
Rare diseases - validation of disease-causing human variants in animal models
The molecular basis of the ever-renewing reptilian dentition using the gecko model
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Postdoctoral Fellows
Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - May 2019)
Mouse and human genetic data suggests that Wnt5a is required for jaw development but the specific role in facial skeletogenesis and morphogenesis is unknown. The aim of this thesis is to study functions of WNT5A during mandibular development in chicken embryos.We initially determined that WNT5A is expressed in developing Meckel's cartilage but in mature cartilage expression was decreased to background. This pattern suggested that WNT5A is regulating chondrogenesis so to determine whether initiation, differentiation or maintenance of matrix was affected I used primary cultures of mandibular mesenchyme. I found that Wnt5a conditioned media allowed normal initiation and differentiation of cartilage but the matrix was subsequently lost. Collagen II and aggrecan, two matrix markers, were decreased in treated cultures. Degradation of matrix was due to the induction of metalloproteinases, MMP1, MMP13, and ADAMTS5 and was rescued by an MMP antagonist. The effects of Wnt5a on cartilage were mainly due to stimulation of the non-canonical JNK/PCP pathway as opposed to antagonism of the canonical Wnt pathway.To increase the clinical relevance of my work I studied the functional consequences of two human WNT5A mutations (C182R and C83S) causing human Robinow syndrome. Retroviruses containing mutant and wild-type versions of WNT5A caused shortening of beaks and limbs; however, the phenotypes were more frequent and severe with mutations. Mechanisms responsible for micrognathia were assessed. Decreased cell proliferation and impaired chondrocyte organization and intercalation were seen with all constructs. The effects of mutant proteins on the migration of mesenchymal cells were tested in organ cultures of the mandible. The C83S and to a lesser extent C182R forms of WNT5A inhibited the normal migration of dye-labeled mesenchymal cells. The lack of cell migration was similar to that reported in Wnt5a null mice and therefore suggested that the WNT5A mutations are causing a loss-of-function.We conclude that WNT5A is required during early chondrogenesis to block canonical signaling thereby allowing cartilage to form. In addition, WNT5A is required for cells to migrate within the mandible and perhaps to form the elongated shape of the lower jaw. Finally WNT5A in conditions of excess has detrimental effects on cartilage integrity.
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Master's Student Supervision (2010 - 2018)
The leopard gecko is an emerging reptilian model for the molecular basis of indefinite tooth replacement. Here we characterize the tooth replacement frequency and pattern of tooth loss in the normal adult gecko. We chose to perturb the system of tooth replacement by activating the Wingless signaling pathway (Wnt). Misregulation of Wnt leads to supernumerary teeth in mice and humans. We hypothesized by activating Wnt signaling with LiCl, tooth replacement frequency would increase. To measure the rate of tooth loss and replacement, weekly dental wax bites of 3 leopard geckos were taken over a 35-week period. The present/absent tooth positions were recorded. During the experimental period, the palate was injected bilaterally with NaCl (control) and then with LiCl. The geckos were to be biological replicates. Symmetry was analyzed with parametric tests (repeated measures ANOVA, Tukey’s post-hoc), while time for emergence and total absent teeth per week were analyzed with non-parametric tests (Kruskal-Wallis ANOVA, Mann-Whitney U post-hoc and Bonferroni Correction). The average replacement frequency was 6-7 weeks and posterior-to-anterior waves of replacement were formed. Right to left symmetry between individual tooth positions was high (>80%) when all teeth were included but dropped to 50% when only absent teeth were included. Two animals were followed for 14 weeks after NaCl injections and 14 weeks after LiCl injections. NaCl did not affect the replacement dentition but LiCl delayed and disrupted the pattern of replacement. The phenotypes were more severe for one animal including 1) increased time before emergence, 2) increased total number of absent teeth per week, 3) a greater effect on anterior teeth and 4) disruption of symmetry. The most affected period began 7 weeks post LiCl injection. At the end of the study, in vitro CT scans of both animals revealed normal patterns of unerupted teeth however there was bone loss in one animal. Gecko tooth replacement is rapid enough to be useful for longitudinal studies. Between-animal variation is high when studying individual teeth therefore each animal should be used as its own control. Future work includes increasing the biological replicates and detailed molecular studies to confirm the effect of LiCl.
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Objectives: In order to study abnormal facial development, reference standards of normal development are required. It is challenging to obtain 3D data on early embryos, since they are comprised of non-differentiated tissue. We used optical projection tomography (OPT) (Bioptonics, UK), which images transparent specimens with UV light. Here we used carefully staged chicken embryos to measure facial morphogenesis over time.Methods: Chicken eggs (n=32) were incubated for 3.5-6 days (stage 20, 24, 28, 29). Embryo heads were fixed in formaldehyde, embedded in agarose, dehydrated in methanol, and then cleared in Benzyl Alcohol Benzyl Benzoate. Embryos were scanned with the OPT, images were reconstructed, and then the head was digitally resliced in the frontal plane using NRecon and CTan. Resliced files were imported into Amira, facial prominences were outlined, and isosurfaces were created. Volumetric measurements were assessed using Amira. Landmarks were applied to the surface of each prominence using Landmark. These landmarks were then superimposed from different embryos using MorphoJ, whereby they underwent Procrustes superimposition, Principal Component Analysis, Canonical Variate Analysis, and Discriminant Function Analysis.Results: Traditional morphometrics revealed that the greatest amount of growth was a 24-fold difference in volume of the lateral nasal prominence between stages 20 and 29, followed by the maxillary, mandibular, and frontonasal mass. Geometric morphometrics revealed that embryonic facial prominences had minimal changes in shape between stages 20 and 24, however, after this time, there was more separation of the data in morphospace. Strikingly, the greatest morphological change was between stages 28 and 29, which was only 12 hours apart. This rapid change suggests that other mechanisms in addition to cell proliferation are involved. In addition, the data show that major morphological changes precede lip fusion. Therefore, we can pinpoint our studies to stage 28, when critical events in the mesenchyme are taking place. Conclusion: Embryonic chicken facial prominences undergo major shape changes. Each prominence varies in morphology with respective stage, with the frontonasal mass and mandibular prominence having the most dynamic shape changes.
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Though most dentate vertebrates replace their teeth at least once in the course of their lives, the process of tooth replacement is poorly understood. This is mainly because the major tooth development model is the mouse which only has one generation of teeth. Our previous work suggested that tooth renewal in geckos might involve dental epithelial stem cells and that these putative stem cells become transit- amplifying cells when exposed to canonical WNTs. Here we further investigate this idea using adult leopard geckos (Eublepharis macularius). To further previous findings from our lab that the dental apparatus is a WNT responsive tissue we perturbed the WNT pathway by agonist and antagonist organ cultures of oral tissue explants. BIO stimulated proliferation at an intermediate concentration of 20 μM but not at higher or lower concentrations. This suggests that in vivo, cells are responding to gradients of WNT activity. We also looked at associated BMP and FGF pathways via in situ histology and organ culture manipulation respectively and found alternating patterns of gene expression. We then mapped areas of high canonical WNT signaling and found that nuclear staining for phospho beta catenin was principally found in the outer enamel epithelium and successional lamina. We moved to an in vivo strategy to allow for better tissue survival. Palatal injections of LiCl or the control reagent NaCl were delivered to the base of the maxillary teeth. We found that LiCl increased proliferation in the successional lamina and cervical loops, areas that normally have higher proliferation. We conclude that certain regions of the dental epithelium are sensitive to change in canonical WNT signaling and that this signaling is potentially kept to a localized region via BMP inhibition of the WNT pathway. Regions of the dental lamina that contain putative stem cells may require signals in addition to WNTs to stimulate the formation of transit amplifying cells. Future work will further elucidate the many signaling cascades required for tooth succession to occur.
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No abstract available.
Vertebrate craniofacial development and speciation has been studied in great detail, with major emphasis placed on mammalian species and highly derived archosaurs (birds). However, less is known about reptiles and in particular turtles. Turtles are speculated as to have retained many ancestral features of amniotes. Therefore, studying the Testudine (turtle) order not only helps to better understand amniote head development, but also the derivation of modern form. This thesis will investigate the formation of the hard palate in a representative turtle species, E. subglobosa, not only because of its evolutionary significance but also because this region is frequently affected in orofacial clefting. Origins of the palatine bones were first examined since other amniotes form these bones within outgrowths of the maxillary prominence, or the palatal shelves. Surprisingly no palatal shelves were found at the position or time when they should have been forming. Instead palatine bones condensed directly in the mesenchyme beneath the nasal cavity Furthermore there was no evidence from cell proliferation or apoptosis analysis of the maxillary prominences that vestigial shelves were ever present. The hypothesis following was that gene expression in the maxillary prominences might be different in turtles compared to the chicken or mouse in which shelves do form. I found no major differences but interestingly several of the genes I studied were also markers of the primitive stomodeum. Results show the turtle retains gene expression patterns of the chicken stomodeum, the primitive oral roof before palatal shelf formation, suggesting the turtle oral roof is still primitive in nature rather than advanced in other amniotes. This unfamiliar mechanism of hard palate development with no vestigial traits of palatal shelf formation supports arguments for a more basal placement of the turtle in the phylogenetic tree. Contrary to these findings, the similarity in gene expression and sequence to the chicken argues for a more derived placement closer to the archosaurs. While these present results do not allow for confident placement of the turtle as more basal or derived in the amniote tree, the data collected shows that ontological studies can help shed light on evolutionary debates.
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The aim of this thesis is to study the effects of reducing retinoic acid (RA) levels in the embryonic face on jaw morphogenesis. One member of the Cytochrome P26 class of enzymes, CYP26A1, which degrades retinol products, was locally overexpressed in chicken embryos. I hypothesized that lowering RA levels would either affect jaw patterning, cell survival and/or cytodifferentiation. Chicken embryos at stage 15 and 20 (E2.5, 3.5) were injected with RCAS
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Publications
- Getting out of an egg: Merging of tooth germs to create an egg tooth in the snake (2019)
Developmental Dynamics, - JDR Historical Highlights #10 (2019)
Journal of Dental Research, 98 (10), 1063--1065 - Robinow syndrome skeletal phenotypes caused by the WNT5AC83S variant are due to dominant interference with chondrogenesis (2019)
Human Molecular Genetics, - Shedding new light on the mysteries of tooth eruption (2019)
Proceedings of the National Academy of Sciences, 116 (2), 353--355 - Coordination of bilateral tooth replacement in the juvenile gecko is continuous with in ovo patterning (2018)
Evolution & Development, 20 (2), 51--64 - Abnormal WNT5A Signaling Causes Mandibular Hypoplasia in Robinow Syndrome. (2017)
Journal of dental research, - Craniofacial defects and cleft lip and palate (2017)
Wiley, - Design of lipid nanoparticles for in vitro and in vivo delivery of plasmid DNA. (2017)
Nanomedicine : nanotechnology, biology, and medicine, - Face Forward: Gene Variants, Pathways, and Therapies for Craniofacial Anomalies. (2017)
Journal of dental research, - Methyltransferase G9A Regulates Osteogenesis via Twist Gene Repression. (2017)
Journal of dental research, - BMP signaling regulates the fate of chondro-osteoprogenitor cells in facial mesenchyme in a stage-specific manner. (2016)
Developmental dynamics : an official publication of the American Association of Anatomists, - MORN5 Expression during Craniofacial Development and Its Interaction with the BMP and TGFβ Pathways. (2016)
Frontiers in physiology, - Pannexin 3 is required for late stage bone growth but not for initiation of ossification in avian embryos. (2016)
Developmental dynamics : an official publication of the American Association of Anatomists, - Recent insights into the morphological diversity in the amniote primary and secondary palates (2016)
Developmental Dynamics, 244 (12), 1457-1468 - Analysis of human soft palate morphogenesis supports regional regulation of palatal fusion (2015)
Journal of Anatomy, 227 (4), 474-486 - Diversity in primary palate ontogeny of amniotes revealed with 3D imaging (2015)
Journal of Anatomy, 226 (5), 420-433 - Identification and functional analysis of novel facial patterning genes in the duplicated beak chicken embryo (2015)
Developmental Biology, 407 (2), 275-288 - Periodicity and dynamics of tooth replacement from a longitudinal study of leopard geckos (2015)
Integrative and Comparative Biology, 55, E70 - Avian facial morphogenesis is regulated by c-Jun N-terminal Kinase/Planar Cell Polarity (JNK/PCP) wingless-related (WNT) signaling (2014)
Journal of Biological Chemistry, 289 (35), 24153-24167 - Comparative studies on the ontogeny of the primary palate and nasal cavities in birds and mammals (2014)
Integrative and Comparative Biology, 54, E1 - Divergent palate morphology in turtles and birds correlates with differences in proliferation and BMP2 expression during embryonic development (2014)
Journal of Experimental Zoology Part B: Molecular and Developmental Evolution, 322 (2), 73-85 - Biology of tooth replacement in amniotes (2013)
International Journal of Oral Science, 5 (2), 66-70 - Craniofacial ontogeny in turtles: the role of bone morphogenetic protein in the loss of palatal shelves (2013)
Integrative and Comparative Biology, 53, E1 - Dual functions for WNT5A during cartilage development and in disease (2013)
Matrix Biology, 32 (5), 252-264 - Expression, function and regulation of Evi-1 during embryonic avian development (2013)
- Reptilian Tooth Regeneration (2013)
Stem Cells in Craniofacial Development and Regeneration, , 135-151 - Sox2 marks epithelial competence to generate teeth in mammals and reptiles (2013)
Development (Cambridge), 140 (7), 1424-1432 - The western painted turtle genome, a model for the evolution of extreme physiological adaptations in a slowly evolving lineage (2013)
Genome biology, 14 (3) - Development of high-concentration lipoplexes for in vivo gene function studies in vertebrate embryos (2011)
Developmental Dynamics, 240 (9), 2108-2119 - Reptilian tooth development (2011)
Genesis, 49 (4), 247-260 - Tmem26 is dynamically expressed during palate and limb development but is not required for embryonic survival (2011)
PLoS ONE, 6 (9) - Unicuspid and Bicuspid Tooth Crown Formation in Squamates (2011)
Journal of Experimental Zoology Part B-Molecular and Developmental Evolution, 316B (8), 598-608 - A network of Wnt, hedgehog and BMP signaling pathways regulates tooth replacement in snakes (2010)
Developmental Biology, 348 (1), 130-141 - Autocrine and paracrine Shh signaling are necessary for tooth morphogenesis, but not tooth replacement in snakes and lizards (Squamata) (2010)
Developmental Biology, 337 (1), 171-186 - Identification of putative dental epithelial stem cells in a lizard with life-long tooth replacement (2010)
Development, 137 (21), 3545-3549 - Spatiotemporal localization of periostin and its potential role in epithelial-mesenchymal transition during palatal fusion (2010)
Cells Tissues Organs, 193 (1-2), 53-63 - Synaptic localization of neuroligin 2 in the rodent retina: Comparative study with the dystroglycan-containing complex (2010)
Journal of Neuroscience Research, 88 (4), 837-849 - The function and regulation of TBX22 in avian frontonasal morphogenesis (2010)
Developmental Dynamics, 239 (2), 458-473 - Whole genome microarray analysis of chicken embryo facial prominences (2010)
Developmental Dynamics, 239 (2), 592-597 - Expression of WNT signalling pathway genes during chicken craniofacial development (2009)
Developmental Dynamics, 238 (5), 1150-1165 - How snakes and lizards replace their teeth: Molecular and embryological scrutiny of tooth cycling in squamates (2009)
Integrative and Comparative Biology, 49, E70 - Novel skeletogenic patterning roles for the olfactory pit (2009)
Development, 136 (2), 219-229 - The metalloendopeptidase gene Pitrm1 is regulated by hedgehog signaling in the developing mouse limb and is expressed in muscle progenitors (2009)
Developmental Dynamics, 238 (12), 3175-3184 - Expression and regulation of the decoy bone morphogenetic protein receptor BAMBI in the developing avian face (2008)
Developmental Dynamics, 237 (5), 1500-1508 - Expression of the NET family member Zfp503 is regulated by hedgehog and BMP signaling in the limb (2008)
Developmental Dynamics, 237 (4), 1172-1182 - FGF signals from the nasal pit are necessary for normal facial morphogenesis (2008)
Developmental Biology, 318 (2), 289-302 - Initiation and patterning of the snake dentition are dependent on Sonic Hedgehog signaling (2008)
- An endogenous retinoic acid gradient is used to set up rostrocaudal upper beak pattern (2007)
Journal of Morphology, 268 (12), 1054 - Egg tooth development in the snake (2007)
European Cells and Materials, 14 (SUPPL) - Embryonic development of Python sebae - I: Staging criteria and macroscopic skeletal morphogenesis of the head and limbs (2007)
Zoology, 110 (3), 212-230 - Embryonic development of Python sebae - II: Craniofacial microscopic anatomy, cell proliferation and apoptosis (2007)
Zoology, 110 (3), 231-251 - Gene discovery in craniofacial development and disease - Cashing in your chips (2007)
Clinical Genetics, 71 (2), 109-119 - Reptilian evo-devo: Replacement tooth formation in the bearded dragon Pogona vitticeps (2007)
Journal of Morphology, 268 (12), 1080 - Cell dissociation experiments reveal that positional information operates in the chicken frontonasal mass (2006)
Genesis, 44 (3), 105-114 - Comparative ontogeny and phylogeny of the upper jaw skeleton in amniotes (2006)
Developmental Dynamics, 235 (5), 1230-1243 - Evolutionary conservation and murine embryonic expression of the gene encoding the SERTA domain-containing protein CDCA4 (HEPP) (2006)
Gene, 374 (1-2), 153-165 - Retinoid signaling determines germ cell fate in mice (2006)
Science, 312 (5773), 596-600 - A new origin for the maxillary jaw (2004)
- Control of retinoic acid synthesis and FGF expression in the nasal pit is required to pattern the craniofacial skeleton (2004)
Developmental Biology, 276 (2), 313-329 - Upper beak truncation in chicken embryos with the cleft primary palate mutation is due to an epithelial defect in the frontonasal mass (2004)
Developmental Dynamics, 230 (2), 335-349 - About face: Signals and genes controlling jaw patterning and identity in vertebrates (2003)
BioEssays, 25 (6), 554-568 - Endogenous bone morphogenetic proteins regulate outgrowth and epithelial survival during avian lip fusion (2002)
Development, 129 (19), 4647-4660 - Isolation and characterisation of the chick orthologue of the Opitz syndrome gene, Mid1, supports a conserved role in vertebrate development (2002)
International Journal of Developmental Biology, 46 (4 SPE), 441-448 - Signalling via type IA and type IB bone morphogenetic protein receptors (BMPR) regulates intramembranous bone formation, chondrogenesis and feather formation in the chicken embryo (2002)
International Journal of Developmental Biology, 46 (2), 243-253 - Noggin and retinoic acid transform the identity of avian facial prominences (2001)
Nature, 414 (6866), 909-912 - Locally released retinoic acid repatterns the first branchial arch cartilages in vivo (2000)
Developmental Biology, 222 (1), 12-26 - Chicken Transcription Factor AP-2: Cloning, Expression and Its Role in Outgrowth of Facial Prominences and Limb Buds (1997)
Developmental Biology, 188 (2), 248-266 - Effect of Fibroblast Growth Factors on Outgrowth of Facial Mesenchyme (1997)
Developmental Biology, 189 (1), 135-147 - Epithelium is required for maintaining FGFR-2 expression levels in facial mesenchyme of the developing chick embryo (1997)
Developmental Dynamics, 210 (4), 407-416 - Expression of fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3) in the developing head and face (1997)
Developmental Dynamics, 210 (1), 41-52 - Craniofacial development: Knockout mice take one on the chin (1996)
Current Biology, 6 (4), 364-367 - Head Development: Craniofacial genetics makes headway (1995)
Current Biology, 5 (4), 345-348 - Locally released retinoic acid leads to facial clefts in the chick embryo but does not alter the expression of receptors for fibroblast growth factor (1995)
Journal of Craniofacial Genetics and Developmental Biology, 15 (4), 190-204 - Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes (1995)
Cell, 81 (5), 811-823 - The role of retinoids in normal and abnormal embryonic craniofacial morphogenesis (1993)
Critical Reviews in Oral Biology and Medicine, 4 (1), 93-109 - Development of the spatial pattern of retinoic acid receptor-β transcripts in embryonic chick facial primordia (1992)
Development, 114 (3), 805-813 - Epithelial-mesenchymal interactions in the outgrowth of limb buds and facial primordia in chick embryos (1992)
Developmental Biology, 154 (2), 299-308 - Retinoic acid treatment alters the distribution of retinoic acid receptor-β transcripts in the embryonic chick face (1991)
Development, 111 (4), 1007-1016 - Signals involved in patterning and morphogenesis of the embryonic face. (1991)
Progress in clinical and biological research, 373, 117-131 - Differential growth of facial primordia in chick embryos: Responses of facial mesenchyme to basic fibroblast growth factor (bFGF) and serum in micromass culture (1990)
Development, 109 (2), 341-348 - Epithelia are interchangeable between facial primordia of chick embryos and morphogenesis is controlled by the mesenchyme (1989)
Developmental Biology, 136 (1), 201-210 - The fate of Meckel's cartilage chondrocytes in ocular culture (1988)
Developmental Biology, 129 (1), 48-60 - An immunofluorescence study of chondrogenesis in murine mandibular ectomesenchyme (1987)
Cell Differentiation, 21 (3), 161-173 - Tooth induction and temporal patterning in palatal epithelium of fetal mice (1986)
American Journal of Anatomy, 175 (4), 493-505
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