There are major differences in duration and scale at which limb development and regeneration proceed, raising the question to what extent regeneration is a recapitulation of development. We address this by analyzing skeletal elements using a combination of micro-CT imaging, molecular profiling and clonal cell tracing. We find that, in contrast to development, regenerative skeletal growth is accomplished based entirely on cartilage expansion prior to ossification, not limiting the transversal cartilage expansion and resulting in bulkier skeletal parts. The oriented extension of salamander cartilage and bone appear similar to the development of basicranial synchondroses in mammals, as we found no evidence for cartilage stem cell niches or growth plate-like structures during neither development nor regeneration. Both regenerative and developmental ossification in salamanders start from the cortical bone and proceeds inwards, showing the diversity of schemes for the synchrony of cortical and endochondral ossification among vertebrates.

Astrid Lindgren Children's Hospital Karolinska University Hospital Solna Sweden

Central European Institute of Technology Brno University of Technology Brno 61200 Czech Republic

Department of Biology Wake Forest University Winston Salem NC USA

Department of Cell and Molecular Biology Biomedicum Karolinska Institute Stockholm 17165 Sweden

Department of Genetics Microbiology and Statistics Faculty of Biology University of Barcelona Barcelona Spain

Department of Information Technology Uppsala University Uppsala Sweden

Department of Internal Medicine and Clinical Nutrition University of Gothenburg Göteborg 41346 Sweden

Department of Mathematical Sciences The University of Texas at El Paso El Paso TX 79902 USA

Department of Neuroimmunology Center for Brain Research Medical University Vienna Vienna 1090 Austria

Department of Neuroscience Biomedicum Karolinska Institute Stockholm 17165 Sweden

Department of Orthodontics University of Leipzig Medical Center Leipzig 04103 Germany

Department of Pathology Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou 510080 China

Department of Physiology and Pharmacology Karolinska Institutet Stockholm 17165 Sweden

Department of Women's and Children's Health Karolinska Institute Solna Sweden

Max Planck Institute for Evolutionary Biology Plön 24306 Germany

The Research Institute of Molecular Pathology Vienna 1030 Austria

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