Blassberg R, Patel H, Watson T, Gouti M, Metzis V, Delas MJ, Briscoe J (2020). Sox2 levels configure the WNT response of epiblast progenitors responsible for vertebrate body formation. bioRxiv 2020;12.29.424684. doi: https://doi.org/10.1101/2020.12.29.424684
In this work we reveal regulatory mechanisms, dependent on SOX2, that enable cells to adopt different identities in response to WNT activity.
Semprich CI, Metzis V, Patel H, Briscoe J, Storey KG (2019). ERK1/2 signalling dynamics promote neural differentiation by regulating the polycomb repressive complex. bioRxiv 2019;586719.
In this work we demonstrate the chromatin dynamics and changes in polycomb occupancy that occur at neural genes as cells progress to a spinal cord fate.
Needham J, Metzis V. Heads or tails: Making the spinal cord. Developmental Biology. 2022. https://doi.org/10.1016/j.ydbio.2022.03.002
In this review we highlight embryonic stem cell model systems used to study neural development and the formation of the spinal cord. We discuss how primary regionalisation events impact cell identity and outline key technologies at the forefront of the field.
Exelby K, Herrera-Delgado E, Garcia Perez L, Perez-Carrasco R, Sagner A, Metzis V, Sollich P, Briscoe J. Precision of Tissue Patterning is Controlled by Dynamical Properties of Gene Regulatory Networks. Development. 2021;148(4): dev197566. doi.org/10.1242/dev.197566
By removing a regulatory element controlling Olig2, we demonstrate how this impacts tissue patterning in the developing spinal cord. Read the full story to see how we integrate computational and experimental approaches to test how gene regulatory networks contribute to precise tissue patterns.
Preprint available at doi.org/10.1101/721043
Metzis V, Steinhauser S, Pakanavicius E, Gouti M, Stamataki D, Ivanovitch K, Watson T, Rayon T, Mousavy Gharavy SN, Lovell-Badge R, Luscombe NM, Briscoe J. Nervous System Regionalization Entails Axial Allocation before Neural Differentiation. Cell. 2018;175(4):1105- 1118.e17. doi:10.1016/j.cell.2018.09.040
Preprint available at doi:10.1101/229203
This work provides evidence that the competence to form spinal cord during development is transient, and determined by chromatin remodelling events that take place in cells before they form neural progenitors. The data demonstrate that cells acquire regional identity prior to neural identity, prompting revisions to previous models of neural induction.
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– Simon CS, Hadjantonakis AK. Top to Tail: Anterior- Posterior Patterning Precedes Regional Nervous System Identity. Cell. 2018;175(4):905-907.
Gabrysova L, Alvarez-Martinez M, Luisier R, Cox LS, Sodenkamp J, Hosking C, Perez-Mazliah D, Whicher C, Kannan Y, Potempa K, Wu X, Bhaw L, Wende H, Sieweke MH, Elgar G, Wilson M, Briscoe J, Metzis V, et al. c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4(+) T cells. Nat Immunol. 2018;19(5):497-507.
This work highlights the importance of c-Maf in regulating cytokine gene expression in vivo. By defining the transcriptional targets and chromatin landscape in T cells, these data reveal how context-specific immune responses are elicited by c-Maf under different pathologies.
Lu H, Galeano MCR, Ott E, Kaeslin G, Kausalya PJ, Kramer C, Ortiz-Bruchle N, Hilger N, Metzis V, Hiersche M, et al. Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease. Nat Genet. 2017;49(7):1025-1034
This work identified DZIP1L as a novel gene causing autosomal recessive polycystic kidney disease. We developed mechanistic insight into the disease using human patient fibroblast and both mouse and fish models that recapitulate the disease, revealing the role of DZIP1L in regulating the trafficking of proteins through the transition zone of the primary cilium.
Cortes CR, Metzis V, Wicking C. Unmasking the ciliopathies: craniofacial defects and the primary cilium. Wiley Interdiscip Rev Dev Biol. 2015;4(6):637-53.
In this review, we discuss a major class of congenital defects known as ciliopathies. We highlight the prevalence of craniofacial defects associated with these heterogeneous disorders, and discuss the underlying mechanisms.
Gouti M, Metzis V, Briscoe J. The route to spinal cord cell types: a tale of signals and switches. Trends Genet. 2015;31(6):282-9.
In this review, we focus on the cell fate decisions and signals that promote spinal cord development, highlighting the role of neuromesodermal progenitors that form the posterior part of the embryo.
Metzis V, Courtney AD, Kerr MC, Ferguson C, Rondon Galeano MC, Parton RG, Wainwright BJ, Wicking C. Patched1 is required in neural crest cells for the prevention of orofacial clefts. Human Molecular Genetics. 2013;22:5026-5035
This work demonstrated the role of Hedgehog signalling in the genesis of cleft lip in vivo. We revealed the genetic interactions in neural crest cells and morphogenic processes captured with confocal video microscopy, that direct upper lip morphogenesis in mouse embryos.
Bruce SJ, Butterfield NC, Metzis V, Town L, McGlinn E, Wicking C. Inactivation of Patched1 in the mouse limb has novel inhibitory effects on the chondrogenic program. The Journal of Biological Chemistry. 2010;285:27967-27981
Using an in vitro system to model limb cartilage development, we demonstrate a novel role for Ptch1 in the maintenance of cell integrity during the early phases of cartilage condensation.
Butterfield NC, Metzis V, McGlinn E, Bruce SJ, Wainwright BJ, Wicking C. Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb. Development. 2009;136: 3515-3524
This work revealed the genetic network downstream of Ptch1 responsible for controlling digit number and asymmetry in the mouse limb.
Town L, McGlinn E, Fiorenza S, Metzis V, Butterfield NC, Richman JM, Wicking C. The metalloendopeptidase gene Pitrm1 is regulated by hedgehog signaling in the developing mouse limb and is expressed in muscle progenitors. Developmental Dynamics. 2009;238: 3175-3184
We provide the first characterisation of the expression of Pitrm1, a novel gene regulated by Hedgehog signalling, during embryonic development.
McGlinn E, Richman JM, Metzis V, Town L, Butterfield NC, Wainwright BJ, Wicking C. Expression of the NET family member Zfp503 is regulated by hedgehog and BMP signaling in the limb. Developmental Dynamics. 2008;237: 1172-1182
We document the in vivo expression pattern of Zfp503 in chick and mouse embryos, and show that its strict spatio-temporal pattern in the limb bud is dependent on both Hedgehog and BMP signalling.