• INFRAFRONTIER--providing mutant mouse resources as research tools for the international scientific community.

      INFRAFRONTIER Consortium; Meehan, T. F.; Schughart, Klaus; Helmholtz Centre for infection research, Inhoffenstr. 7, 38124 Braunschweig, Germany. (2015-01)
      The laboratory mouse is a key model organism to investigate mechanism and therapeutics of human disease. The number of targeted genetic mouse models of disease is growing rapidly due to high-throughput production strategies employed by the International Mouse Phenotyping Consortium (IMPC) and the development of new, more efficient genome engineering techniques such as CRISPR based systems. We have previously described the European Mouse Mutant Archive (EMMA) resource and how this international infrastructure provides archiving and distribution worldwide for mutant mouse strains. EMMA has since evolved into INFRAFRONTIER (http://www.infrafrontier.eu), the pan-European research infrastructure for the systemic phenotyping, archiving and distribution of mouse disease models. Here we describe new features including improved search for mouse strains, support for new embryonic stem cell resources, access to training materials via a comprehensive knowledgebase and the promotion of innovative analytical and diagnostic techniques.
    • The transcription factors Nkx2.2 and Nkx2.9 play a novel role in floor plate development and commissural axon guidance.

      Holz, Andreas; Kollmus, Heike; Ryge, Jesper; Niederkofler, Vera; Dias, Jose; Ericson, Johan; Stoeckli, Esther T; Kiehn, Ole; Arnold, Hans-Henning; Cell and Molecular Biology, University of Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany. (2010-12)
      The transcription factors Nkx2.2 and Nkx2.9 have been proposed to execute partially overlapping functions in neuronal patterning of the ventral spinal cord in response to graded sonic hedgehog signaling. The present report shows that in mice lacking both Nkx2 proteins, the presumptive progenitor cells in the p3 domain of the neural tube convert to motor neurons (MN) and never acquire the fate of V3 interneurons. This result supports the concept that Nkx2 transcription factors are required to establish V3 progenitor cells by repressing the early MN lineage-specific program, including genes like Olig2. Nkx2.2 and Nkx2.9 proteins also perform an additional, hitherto unknown, function in the development of non-neuronal floor plate cells. Here, we demonstrate that loss of both Nkx2 genes results in an anatomically smaller and functionally impaired floor plate causing severe defects in axonal pathfinding of commissural neurons. Defective floor plates were also seen in Nkx2.2(+/-);Nkx2.9(-/-) compound mutants and even in single Nkx2.9(-/-) mutants, suggesting that floor plate development is sensitive to dose and/or timing of Nkx2 expression. Interestingly, adult Nkx2.2(+/-);Nkx2.9(-/-) compound-mutant mice exhibit abnormal locomotion, including a permanent or intermittent hopping gait. Drug-induced locomotor-like activity in spinal cords of mutant neonates is also affected, demonstrating increased variability of left-right and flexor-extensor coordination. Our data argue that the Nkx2.2 and Nkx2.9 transcription factors contribute crucially to the formation of neuronal networks that function as central pattern generators for locomotor activity in the spinal cord. As both factors affect floor plate development, control of commissural axon trajectories might be the underlying mechanism.