Research Report 2010 - MDC

Signaling Pathways and Mechanisms in the Nervous SystemStructure of the GroupCarmen Birchmeier-KohlerGroup LeaderProf. Dr. CarmenBirchmeier-KohlerScientific ManagerDr. Michael StrehleSenior ScientistsDr. Thomas MüllerDr. Alistair GarrattScientistsDr. Dominique BröhlDr. Cyril CheretDevelopmental Biology/Signal TransductionWe analyze the functions of signaling molecules and of transcription factors indevelopment of the nervous system and muscle. For this work, we use mice as a modelorganism. The molecular genetics of mice is well developed, and homologous recombinationcombined with embryonic stem cell technology can be used to introduce deletions orinsertions into the genome. A further development of the technique, the Cre/LoxP technology,allows us now to introduce conditional mutations that are restricted to a particular celllineage. We have used these technologies to analyze genes that control myoblast fusion, andshowed that two small G proteins, Rac1 and Cdc42, are essential for the fusion process. Inaddition, we identified the function of several transcription factors in development of thenervous system. Among these is a novel factor, Insm1, that we found unexpectedly to performalso important functions in development of pancreatic beta-cells, the insulin-producingendocrine cells.The role of Insm1 in neuronal developmentRobert Storm, Jochen Welcker, Kira Balueva and ShiqiJia (in collaboration with John Jacob and JamesBriscoe, MRC, London).Insm1 (insulinoma associated antigen) encodes a Znfingerfactor that is transiently expressed in differentiatingneurons throughout the developing nervous system,as well as in endocrine cells of the pancreas andintestine. We generated mice with a targeted mutationto analyze the function of the Insm1 gene. In an initialanalysis, we identified Insm1 as a factor crucial for thedifferentiation of beta-cells in the pancreas. Impairedfunction or loss of pancreatic beta-cells causes diabetes,a prevalent humane disease throughout theworld. In the absence of Insm1, the expression programfor hormones and a plethora of genes coding for proteinsinvolved in secretion and vesicle transport wasdownregulated in beta-cells.However, Insm1 is not only required in endocrine celldevelopment, but is also a crucial component of thetranscriptional network that controls neuronal development.In Insm1 mutant mice, differentiation of sympatho-adrenalprecursors was strongly delayed, whichwas accompanied by reduced proliferation of the precursors.Whereas sympathetic neurons differentiatedlate and in reduced numbers, resulting in small sympatheticganglia, terminal differentiation of adrenal chromaffincells, the major source of noradrenaline, did notoccur. The catecholamine noradrenaline is essential forfetal heart function and survival. Due to a pronouncednoradrenaline deficiency, Insm1 homozygous mutantmice died during mid-gestation, but we could rescuethem by administration of catecholamine intermediates.Analysis of the transcriptional network governingsympatho-adrenal precursor differentiation indicatedthat Insm1 acts downstream of Mash1 (Ascl1) and Phox2b.150 Function and Dysfunction of the Nervous System