Institute of Experimental Medicine CAS

Department of Developmental Biology

Head:

Ondřej Machoň, PhD.

E-mail: ondrej.machon@iem.cas.cz
Phone: +420 241 062 744,
             +420 608 375 868

Department of Developmental Biology focuses on genetic regulation of embryonic development. We use gene conditional knock-out technology in the mouse model to reveal specific roles of selected signaling pathways and transcription factors regulating embryonic development in craniofacial, neural or ear tissues. Studies in mouse are complemented with experiments in zebrafish embryos. Using these experimental organisms we aim to elucidate genetic basis of selected human developmental defects.

Deputy Head:

Simona Vojtěchová
E-mail: simona.vojtechova@iem.cas.cz
Phone: +420 241 062 603

Research Scientists:

Ondřej Machoň, PhD.

PhD. Students:

Jaroslav Fábik, MSc.
Viktorie Psutková, MSc.

Undergraduate Students:

Jana Limbergová
Miroslav Matějček

Technicians:

Simona Vojtěchová, MSc 

Important results in 2020

1.  Neural crest cells require Meis2 for patterning the mandibular arch via the Sonic hedgehog pathway.

Deletion of Meis2 in the neural crest using Wnt1-Cre2 leads to several craniofacial defects such as hypoplastic tongue, absent submandibular gland and short mandible. The defects come from impaired molecular patterning of the first pharyngeal arch at earlier stages and reduced Shh signalling. The paper describes molecular network linking Meis2 mediated transcription and Shh signalling in neural crest cells during craniofacial development.

Publication   Fabik J, Kovacova K, Kozmik Z, Machon O. Neural crest cells require Meis2 for patterning the mandibular arch via the Sonic hedgehog pathway. Biol Open. 2020 Jul 2;9(6):bio052043. 

2. The transcriptional regulator MEIS2 sets up the ground state for palatal osteogenesis in mice. 

Conditional knock-out of Meis2 in the neural crest leads to abnormal development of the upper jaw, so called cleft palate. We show that Meis2 transcription factor controls osteogenesis by direct regulation of crucial osteogenic factors Shox2, Runx2 or Pbx1. This paper provides a mechanistic insight into several human developmental craniofacial pathologies with mapped mutations in the Meis2 gene.

Publikace: Wang L, Tang Q, Xu J, Li H, Yang T, Li L, Machon O, Hu T, Chen Y. The transcriptional regulator MEIS2 sets up the ground state for palatal osteogenesis in mice. J Biol Chem. 2020 Apr 17;295(16):5449-5460. 

3. Developmental variability channels mouse molar evolution. 

Morphology of molars was compared in mouse strains DUHi and FVB. While DUHi tend to have long molars, FVB display short and wide ones. These variations are already observed during embryonic development in tooth germs labeled with Shh expression. These findings show how early differences during development in genetically identical animals can lead to small variations in tooth form and size in adults.

Publication: Hayden L, Lochovska K, Sémon M, Renaud S, Delignette-Muller ML, Vilcot M, Peterkova R, Hovorakova M, Pantalacci S. Developmental variability channels mouse molar evolution. Elife. 2020 Feb 12;9:e50103. doi: 10.7554/eLife.50103. 

Important results in 2019

1. A radical switch in clonality reveals a stem cell niche in the epiphyseal growth plate

 

Longitudinal bone growth in children is sustained by cartilage growth plates providing a continuous supply of chondrocytes for endochondral ossification. We characterized a new stem cell population of chondroprogenitors that develops postnatally in the epiphyseal growth plate under a secondary ossification centre, and provides a continuous supply of chondrocytes over a long period. This niche is maintained by Shh and mTORC1 signalling pathways.

Publication:  Newton PT, Li L, Zhou B, Schweingruber C, Hovorakova M, Xie M, Sun X, Sandhow L, Artemov AV, Ivashkin E, Suter S, Dyachuk V, El Shahawy M, Gritli-Linde A, Bouderlique T, Petersen J, Mollbrink A, Lundeberg J, Enikolopov G, Qian H, Fried K, Kasper M, Hedlund E, Adameyko I, Sävendahl L, Chagin AS. Nature. 2019 Mar;567(7747):234-238. doi: 10.1038/s41586-019-0989-6.

 

Important results in 2018

1. Tcf7L2 is essential for neurogenesis in the developing mouse neocortex.

We detected abundant expression of two transcrtiption factors mediating canonical Wnt signalling, Tcf7L1 and Tcf7L2, in the ventricular germinal zone of the embryonic neocortex. Conditional knock-out analysis showed that Tcf7L2 is the principal Wnt mediator important for maintenance of progenitor cell identity. In the absence of Tcf7L2, the Wnt activity is reduced and the neuroepithelial structure is severed due to the loss of apical adherens junctions. This results in decreased proliferation of radial glial cells and intermediate progenitors and hypoplastic forebrain.

Publikation: Chodelkova, O., Masek, J. Korinek, V., Kozmik, Z., Machon, O. Tcf7L2 is essential for neurogenesis in the developing mouse neocortex. Neural Dev. 2018 May 11;13(1):8. doi: 10.1186/s13064-018-0107-8.

2.  Signals from the brain and olfactory epithelium control shaping of the mammalian nasal capsule cartilage.

Here, we reveal that cartilaginous nasal capsule is shaped by signals generated by neural structures: brain and olfactory epithelium. Brain-derived SHH enables the induction of nasal septum and posterior nasal capsule, whereas the formation of a capsule roof is controlled by signals from the olfactory epithelium. Experiments with mutant mice revealed that the regulatory regions controlling production of SHH in the nervous system contribute to facial cartilage morphogenesis, which might be a mechanism responsible for the adaptive evolution of animal faces and snouts

Publikace: Kaucka M, Petersen J, Tesarova M, Szarowska B, Kastriti ME, Xie M, Kicheva A, Annusver K, Kasper M, Symmons O, Pan L, Spitz F, Kaiser J, Hovorakova M, Zikmund T, Sunadome K, Matise MP, Wang H, Marklund U, Abdo H, Ernfors P, Maire P, Wurmser M, Chagin AS, Fried K, Adameyko I. Signals from the brain and olfactory epithelium control shaping of the mammalian nasal capsule cartilage. Elife. 2018 Jun 13;7. pii: e34465. doi: 10.7554/eLife.34465.

Important results in 2016

 

Population of cells originating in the area giving rise to teeth forms also a part of the oral vestibule externally to teeth

We have shown in this study that the early events in the developing anterior area of the mandible are common to the prospective functional incisor primordia and for the non-dental tissue - the vestibular epithelium, forming the oral vestibule. Because these cells give rise to teeth, they can keep their odontogenic potential under pathological conditions and become a source of pathologies in non-dental areas externally to dentition, such as peripheral odontomas containing dental tissues or small teeth.

  vb2016cz-jpg-370978526

The development of the oral vestibule with contribution of cells of the early signaling center of mouse incisor. Dissociated epithelium (A) and histological section (B) show the cell population (blue) from the early signaling center of dental epithelium (DE) of the mouse incisor localized not only in the tooth germ of functional incisor (FI) but also in the vestibular epithelium (VE) giving rise to the oral vestibule (VO), development of which is shown schematically (C).

Publication:
Hovorakova M, Lochovska K, Zahradnicek O, Domonkosova Tibenska K, Dornhoferova M, Horakova-Smrckova L, Bodorikova S. One Odontogenic Cell-Population Contributes to the Development of the Mouse Incisors and of the Oral Vestibule.PLoS One. 2016 Sep 9;11(9):e0162523. IF: 3,057

 

Important result in 2015

Sprouty gene dosage influences temporal-spatial dynamics of primary enamel knot formation

In normal mice, the signalling centres of a premolar rudimentary bud and the first molar anlage fuse together to commonly form one typical signalling centre (primary enamel knot) of the first molar. With decreasing Sprouty2 and Sprouty4 gene dosages, we observed a non-fusion of the above mentioned signalling centres, with consequent formation of a supernumerary tooth primordium from the individually developing premolar bud. Our findings significantly contribute to existing knowledge about supernumerary tooth formation.

  2015peterkacz

Development of a supernumerary tooth in mouse embryos.

Publication:
Lochovska K, Peterkova R, Pavlikova Z, Hovorakova M. Sprouty gene dosage influences temporal-spatial dynamics of primary enamel knot formation. BMC Dev Biol. 2015 Apr 22;15:21. doi: 10.1186/s12861-015-0070-0

 

Important result in 2014

Three-dimensional analysis of the early development of the dentition

The present reviews survey data provided by 20 years research of odontogenesis in the laboratory mouse and in humans. Our results disprove the generally accepted concept of dentition morphogenesis, and offer new interpretations of results of studies on interactions between dental epithelium and mesenchyme, and on molecular control of tooth development in the mouse model. Such knowledge is important for future methods aimed to development of tooth biological replacements, when a tooth implant resulting from controlled differentiation of living cells will be anchored to a jaw.

2014peterka1cz

Summarized data on developing dentition and oral vestibule in human and their tentative comparison with developing teeth in fishes. (A) Embryological textbooks present two parallel U-shaped ridges in human embryos: DL - dental lamina (giving rise to the deciduous dentition) and VL - vestibular lamina or labio-gingival band (where oral vestibule will form). (B) Summarization of our data by 3D reconstructions document no continuous vestibular lamina exists. Instead, a set of discontinuous epithelial structures (ridges and bulges) transiently occurs externally to the dental epithelium. Red - dental epithelium. Yellow or blue – vestibular epithelium. c, m1, m2 – the deciduous canine, first and second molar, respectively. AC – the accessory cap-shaped structure. (D) The schematic pattern of tooth rows (“Zahnreihen”) in fishes. The empty rings and black spots indicate the older and younger teeth, respectively, new teeth are formed at the posterior end of each Zahnreihen. (E) Dental and vestibular epithelium in 8 weeks old human embryonic maxilla in a 3D reconstruction viewed from mesenchymal aspect. Note the reiterative fusions (white asterisks) between the dental epithelium and particular ridges of the vestibular epithelium. c, m1 – the deciduous canine and the first molar, respectively.

2014peterka2cz

Correlation between Shh signaling centers and developing teeth in the mandible of WT mice. Insert: Shh in situ hybridization of the whole mandible at embryonic day 12.5. Rectangles – functional teeth; round and oval shapes – Shh expression domains of developing teeth. Classical view: According to the literature, Shh expression is present in two signaling centers in each mandible half. The anterior one corresponds to the incisor primordium (I), the posterior one corresponds to the first molar (M1) until embryonic day 14. New view: According to the summary of our recent results, the Shh expression appears in several domains along the antero-posterior jaw axes of the lower jaw. The earlier-appearing domains correspond to the rudimentary tooth primordia in the incisor (pt-green) and cheek (MS-blue; R2-red) regions. Later, the primordia of functional teeth with their signaling centers appear: incisor (I-yellow), first molar (M1-yellow). The signaling centers MS, R2 and M1 appear successively in the distal direction. In adults, the functional M1 takes its origin with the contribution of R2 rudiment (red rectangle). A minor contribution of MS rudiment cannot be excluded (blue rectangle).

Collaboration: Lesot Hervé, Institut National de la Sante et de la Recherche Medicale, UMR 1109, Team ‘Osteoarticular and Dental Regenerative NanoMedicine’, Strasbourg, France

Publications:

  • Peterkova R, Hovorakova M, Peterka M, Lesot H. Three-dimensional analysis of the early development of the dentition. Aust Dent J. 2014, 59 Suppl 1:55-80. IF: 1.482
  • Lesot H, Hovorakova M, Peterka M, Peterkova R. Three-dimensional analysis of molar development in the mouse from the cap to bell stage. Aust Dent J. 2014, 59 Suppl 1:81-100. IF: 1.482

2021

Kaiser K, Jang A, Kompanikova P, Lun MP, Prochazka J, Machon O, Dani N, Prochazkova M, Laurent B, Gyllborg D, van Amerongen R, Fame RM, Gupta S, Wu F, Barker RA, Bukova I, Sedlacek R, Kozmik Z, Arenas E, Lehtinen M, Bryja V. MEIS-WNT5A axis regulates development of 4th ventricle choroid plexus. Development 2021

2020

Fabik J, Kovacova K, Kozmik Z, Machon O. Neural crest cells require Meis2 for patterning the mandibular arch via the Sonic hedgehog pathway. Biology Open (2020) 9, bio052043. doi:10.1242/bio.052043

Wang L, Tang Q, Xu J, Li H, Yang T, Li L, Machon O, Hu T, Chen Y. The transcriptional regulator Meis2 sets up the ground state for palatal osteogenesis in mice. J Biol Chem. 2020 Mar 13. doi: 10.1074/jbc.RA120.012684. 

Hayden L, Lochovska K, Sémon M, Renaud S, Delignette-Muller ML, Vilcot M, Peterkova R, Hovorakova M, Pantalacci S. Developmental variability channels mouse molar evolution. Elife. 2020 Feb 12;9. pii: e50103. doi: 10.7554/eLife.50103.

2019

Newton PT, Li L, Zhou B, Schweingruber C, Hovorakova M, Xie M, Sun X, Sandhow L, Artemov AV, Ivashkin E, Suter S, Dyachuk V, El Shahawy M, Gritli-Linde A, Bouderlique T, Petersen J, Mollbrink A, Lundeberg J, Enikolopov G, Qian H, Fried K, Kasper M, Hedlund E, Adameyko I, Sävendahl L, Chagin AS. A radical switch in clonality reveals a stem cell niche in the epiphyseal growth plate. Nature. 2019 Mar;567(7747):234-238. doi: 10.1038/s41586-019-0989-6.

Vesela B, Svandova E, Hovorakova M, Peterkova R, Kratochvilova A, Pasovska M, Ramesova A, Lesot H, Matalova E. Specification of Sprouty2 functions in osteogenesis in  in vivo context. Organogenesis. 2019;15(4):111-119. doi: 10.1080/15476278.2019.1656995.

Sadier A, Twarogowska M, Steklikova K, Hayden L, Lambert A, Schneider P, Laudet V, Hovorakova M, Calvez V, Pantalacci S. Modeling Edar expression reveals the hidden dynamics of tooth signaling center patterning.  PLoS Biol. 2019 Feb 7;17(2):e3000064. doi: 10.1371/journal.pbio.3000064. 

2018

Fulka, H., Langerova, A. Nucleoli in embryos: a central structural platform for embryonic chromatin remodeling? Review. Chromosome Res 2018, https://doi.org/10.1007/s10577-018-9590-3

Peterka, M., Likovsky, Z., Panczak, A., Peterkova, M. Long-term significant seasonal differences in the numbers of new-borns with an orofacial cleft in the Czech Republic - a retrospective study. BMC Pregnancy Childbirth 2018, 28;18(1):348. doi: 10.1186/s12884-018-1981-0

Zidek, R., Machon, O., Kozmik, Z. Wnt/beta-catenin signalling is necessary for gut differentiation in marine annelid, Platynereis dumerilii. EvoDevo 2018, 9: 14.

Kaucka, M., Petersen, J., Tesarova, M., Szarowska, B., Kastriti, M.E., Xie, M., Kicheva, A., Annusver, K., Kasper, M., Symmons, O., Pan, L., Spitz, F., Kaiser, J., Hovorakova, M., Zikmund, T., Sunadome, K., Matise, M.P., Wang, H., Marklund, U., Abdo, H., Ernfors, P., Maire, P., Wurmser, M., Chagin, A.S., Fried, K., Adameyko, I. Signals from the brain and olfactory epithelium control shaping of the mammalian nasal capsule cartilage. Elife 2018 Jun 13;7. pii: e34465. doi: 10.7554/eLife.34465.

Hovořáková, M. , Lesot, H., Peterka, M., Peterková, R. Early development of the human dentition revisited. Review. J. Anat. 2018 May 10. doi: 10.1111/joa.12825.

Chodelková, O., Mašek, J., Kořínek, V., Kozmik, Z., Machoň, O. Tcf7L2 is essential for neurogenesis in the developing mouse neocortex. Neural Dev. 2018 May 11;13(1):8. doi: 10.1186/s13064-018-0107-8.

2017

Pantalacci, S., Guéguen. L., Petit. C., Lambert. A., Peterková, R., Sémon. M. (2017) Transcriptomic signatures shaped by cell proportions shed light on comparative developmental biology. Genome Biol. 18(1): 29. doi: 10.1186/s13059-017-1157-7.

Fons Romero, J.M., Star. H., Lav, R., Watkins, S., Harrison, M., Hovořáková, M., Headon. D., Tucker. A.S. (2017) The Impact of the Eda Pathway on Tooth Root Development. J Dent Res.  96(11):1290-1297. doi: 10.1177/0022034517725692.

2016

Dosedělová, H., Štěpánková, K., Zikmund, T., Lesot, H., Kaiser, J., Novotný,K., Štembírek, J., Knotek, Z., Zahradníček, O., Buchtová, M.: (2016) Age-related changes in the tooth-bone interface area of acrodont dentition in the chameleon. J. Anat., 229(3): 356-368.

Hovořáková, M., Lochovská, K., Zahradníček, O. , Domonkosová, T. K., Dornhoferová, M., Hořáková-Smrčková, L., Bodoriková, S.: (2016) One Odontogenic Cell-Population Contributes to the Development of the Mouse Incisors and of the Oral Vestibule. PLoS One, 11(9): e0162523.

Khannoon, E. R., Zahradníček, O.: (2015) Postovipositional development of the sand snake Psammophis sibilans (Serpentes:Lamprophiidae) in 1 comparison with other snake species. Acta Zool., IN PRESS

Liška, F., Peterková, R., Peterka, M., Landa, V., Zídek, V., Mlejnek, P., Šilhavý, J., Šimáková, M., Křen, V., Starker, C.G., Voytas, D.F., Izsvák, Z., Pravenec, M.: (2016) Targeting of the Plzf Gene in the Rat by Transcription Activator-Like Effector Nuclease Results in Caudal Regression Syndrome in Spontaneously Hypertensive Rats. PLoS One, 11(10): e0164206.

Mašek, J., Machoň, O., Kořínek, V., Taketo M. M., Kozmik, Z. (2016) Tcf7L1 protects the anterior neural fold from adopting the neural crest fate. Development 143, 2206-2216

2015

Blackburn, J., Kawasaki, K., Porntaveetus, T., Kawasaki, M., Otsuka-Tanaka, Y., Miake, Y., Ota, Masato., Watanebe, M., Hishinuma, M., Nomoto, T., Oommen, S., Ghafoor, S., Harada, F., Nozawa-Inoue, K., Maeda, T., Peterková, R., Lesot, H., Inoue, J., Akiyama, T., Schmidt-Ulrich, R., Liu, B., Hu, Y., Page, A., Ramírez, Á., Sharpe, P., Ohazama, A.: (2015) Excess NF-kB induces ectopic odontogenesis in embryonic incisor epithelium. J. Dent. Res. 94(1): 121-128.

Khannoon, E. R., Zahradníček, O.: (2015) Postovipositional development of the sand snake Psammophis sibilans (Serpentes:Lamprophiidae) in1 comparison with other snake species. Acta Zoologica (Stockholm) IN PRESS

Lochovská, K., Peterková, R., Pavliková, Z., Hovoraková, M.: (2015) Sprouty gene dosage influences temporal-spatial dynamics of primary enamel knot formation. BMC Dev Biol. 15: 21.

Machoň, O. , Mašek, J., Machoňová, O., Krauss, S., Kozmik, Z. (2016) Meis2 is essential for cranial and cardiac neural crest cell development. BMC Dev Biol. DOI 10.1186/s12861-015-0093-6

Rusková, H., Bejdová, S., Peterka, M., Krajíček, V., Velemínská, J.: (2015) 3-D shape analysis of palatal surface in patients with unilateral complete cleft lip and palate. J Craniomaxillofac Surg.42(5):e140-147.

2014

Lesot, H., Hovořáková, M., Peterka, M., Peterková, R.: (2014) Three-dimensional analysis of molar development in the mouse from the cap to bell stage. Aust. Dent. J. 59 (Suppl.1): 81-100.

Peterková, R., Hovořáková, M., Peterka, M., Lesot, H.: (2014) Three-dimensional analysis of the early development of the dentition. Aust. Dent. J. 59 (Suppl.1): 55-80.

Rusková, H., Bejdová, S., Peterka, M., Krajíček, V., Velemínská, J.: (2014) 3-D shape analysis of palatal surface in patients with unilateral complete cleft lip and palate. J. Craniomaxillofac Surg. 42(5): e140-147.

Zahradnicek, O., Buchtova, M., Doesedelova, H., TUCKER, A.S. (2014). The development of complex tooth shape in reptiles. Frontiers in Craniofacial Biology 5, 1-7.

2013

Buchtová, M., Zahradníček, O., Balková, S., Tucker, A. S.: (2013) Odontogenesis in the Veiled Chameleon (Chamaeleo calyptratus). Arch. Oral Biol. 58(2): 118-133.

Hovořáková, M., Smrčková, L., Lesot, H., Lochovská, K., Peterka, M., Peterková, R.: (2013) Sequential Shh expression in the development of the mouse upper functional incisor. J. Exp. Zool. Part B. 320(7): 455-464.

Khonsari, R. H., Seppala, M., Pradel, A., Dutel, H., Clément, G., Lebedev, O., Ghafoor, S., Rothová, M., Tucker, A., Maisey, J. G., Fan, C. M., Ohazama, A., Tafforeau, P., Franco, B., Helms, J., Haycraft, C. J., David, A., Janvier, P., Cobourne, M. T., Sharpe, P.T.: (2013) The buccohypophyseal canal is an ancestral vertebrate trait maintained by modulation in sonic hedgehog signaling. BMC Biol.11:70.

Klein, O. D., Oberoi, S., Huysseune, A., Hovořáková, M., Peterka, M., Peterková, R.: (2013) Developmental disorders of the dentition: An update. Am. J. Med. Genet. C. 163(4): 318-332.

Lagronová-Churavá, S., Špoutil, F., Vojtěchová, S., Lesot, H., Peterka, M., Klein, O. D., Peterková, R.: (2013) The Dynamics of Supernumerary Tooth Development Are Differentially Regulated by Sprouty Genes. J. Exp. Zool. Part B. 320(5): 307-320.

Nakatomi, M., Hovořáková, M., Gritli-Linde, A., Blair, H., MacArthur, K., Peterková, R., Lesot, H., Ruiz-Perez, V. L., Goodship, J., Peters, H.: (2013) Evc regulates a symmetric response to Shh signaling in molar development. J. Dent. Res. 92(3): 222-228.

Czech Science Foundation, 18-00514S, Study of the role of transcription factors of the Meis family during the development of neural stem cells, 2018-2020

 Charles University Grant Agency, 1034120, 2019-2021

 Charles University Grant Agency, 340321, 2021-2023. The role of the transcription factor Meis1 during craniofacial development in zebrafish (Danio rerio) 

King's College, London, UK

Institute of Molecular Genetics of the CAS, v. v. i., Prague 

Masaryk University, Brno

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