Mechanisms of Limb Development

Mechanisms of Limb Development

We are interested in basic mechanisms of limb development and how they relate to abnormal development as they are observed in human limb malformations. Limb development is normally governed by a four-dimensional signaling network that directs and controls cell identity and differentiation within the limb. A disturbance of this intricate system by e.g. gene mutations or gene misexpression can result in a myriad of phenotypes including abnormal digit number (polydactyly/oligodactyly), fusion of digits (syndactyly), short or missing elements (brachydactyly), abnormalities of joint formation (synostoses), or abnormalities of dorsoventral patterning. Because of the easy accessibility of the limb, the process of normal and abnormal development can be observed and monitored in appropriate model systems. We investigate limb development in the mouse because signaling pathways and phenotype are highly similar to humans. 

Limb development has been a paradigm to study gene regulatory networks and mechanisms of gene regulation. We are particularly interested in the genomic regulation of gene expression in the 3D space of the developing limb. This involves the function of enhancers and how they interact with their target promoters. An intricate part of this regulation lies in the 3D architecture of the genome and how it changes over time.

Selected publications

Lila Allou, Sara Balzano, Andreas Magg, Mathieu Quinodoz, Beryl Royer-Bertrand, Robert Schöpflin, Wing-Lee Chan, Carlos E. Speck-Martins, Daniel Rocha Carvalho, Luciano Farage, Charles Marques Lourenço, Regina Albuquerque, Srilakshmi Rajagopal, Sheela Nampoothiri, Belinda Campos-Xavier, Carole Chiesa, Florence Niel-Bütschi, Lars Wittler, Bernd Timmermann, Malte Spielmann, Michael I. Robson, Alessa Ringel, Verena Heinrich, Giulia Cova, Guillaume Andrey, Cesar A. Prada-Medina, Rosanna Pescini-Gobert, Sheila Unger, Luisa Bonafé, Phillip Grote Carlo Rivolta Stefan Mundlos✉ & Andrea Superti-Furga
Non-coding deletions identify Maenli lncRNA as a limb-specific En1 regulator
Nature (2021)
Kragesteen BK, Spielmann M, Paliou C, Heinrich V, Schöpflin R, Esposito A, Annunziatella C, Bianco S, Chiariello AM, Jerković I, Harabula I, Guckelberger P, Pechstein M, Wittler L, Chan WL, Franke M, Lupiáñez DG, Kraft K, Timmermann B, Vingron M, Visel A, Nicodemi M, Mundlos S, Andrey G.
Dynamic 3D chromatin architecture contributes to enhancer specificity and limb morphogenesis.
Nat Genet. 2018 Oct;50(10):1463-1473. Epub 2018 Sep 27.
Spielmann M, Lupiáñez DG, Mundlos S.
Structural variation in the 3D genome.
Nat Rev Genet. 2018 Jul;19(7):453-467. Review.

Bianco S, Lupiáñez DG, Chiariello AM, Annunziatella C, Kraft K, Schöpflin R, Wittler L, Andrey G, Vingron M, Pombo A, Mundlos S, Nicodemi M.

Polymer Physics Predicts the Effects of Structural Variants on Chromatin Architecture
Nat Genet. 2018 May;50(5):662-667. Epub 2018 Apr 16.
Andrey G, Mundlos S.
The three-dimensional genome: regulating gene expression during pluripotency and development.
Development. 2017 Oct 15;144(20):3646-3658. Review.
Will AJ, Cova G, Osterwalder M, Chan W-L, Wittler L, Brieske N, Heinrich V, de Villartay J-P, Vingron M, Klopocki E, Visel A, Lupiáñez DG, Mundlos S.
Composition and dosage of a multipartite enhancer cluster control developmental expression of Ihh (Indian hedgehog).
Nat Genet. 2017 Oct;49(10):1539-1545. Epub 2017 Aug 28.
Andrey G, Schöpflin R, Jerković I, Heinrich V, Ibrahim DM, Paliou C, Hochradel M, Timmermann B, Haas S, Vingron M, Mundlos S.
Characterization of hundreds of regulatory landscapes in developing limbs reveals two regimes of chromatin folding.
Genome Res. 2017 Feb;27(2):223-233. Epub 2016 Dec 6.
Jerković I, Ibrahim DM, Andrey G, Haas S, Hansen P, Janetzki C, González Navarrete I, Robinson PN, Hecht J, Mundlos S.
Genome-Wide Binding of Posterior HOXA/D Transcription Factors Reveals Subgrouping and Association with CTCF.
PLoS Genet. 2017 Jan 19;13(1):e1006567. eCollection 2017 Jan.

Franke M, Ibrahim DM, Andrey G, Schwarzer W, Heinrich V, Schöpflin R, Kraft K, Kempfer R, Jerković I, Chan WL, Spielmann M, Timmermann B, Wittler L, Kurth I, Cambiaso P, Zuffardi O, Houge G, Lambie L, Brancati F, Pombo A, Vingron M, Spitz F, Mundlos S.

Formation of new chromatin domains determines pathogenicity of genomic duplications.
Nature 2016 Oct 13;538(7624):265-269. Epub 2016 Oct 5.
Kuss P, Kraft K, Stumm J, Ibrahim D, Vallecillo-Garcia P, Mundlos S, Stricker S.
Regulation of Cell Polarity in the Cartilage Growth Plate and Perichondrium of Metacarpal Elements by HOXD13 and WNT5A.
Dev Biol. 2014 Jan 1;385(1):83-93. Epub 2013 Oct 23.
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