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Defects in the cerebella of conditional Neurod1 null mice correlate with effective Tg(Atoh1-cre) recombination and granule cell requirements for Neurod1 for differentiation

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Abstract

Neurod1 is a crucial basic helix-loop-helix gene for most cerebellar granule cells and mediates the differentiation of these cells downstream of Atoh1-mediated proliferation of the precursors. In Neurod1 null mice, granule cells die throughout the posterior two thirds of the cerebellar cortex during development. However, Neurod1 is also necessary for pancreatic β-cell development, and therefore Neurod1 null mice are diabetic, which potentially influences cerebellar defects. Here, we report a new Neurod1 conditional knock-out mouse model created by using a Tg(Atoh1-cre) line to eliminate Neurod1 in the cerebellar granule cell precursors. Our data confirm and extend previous work on systemic Neurod1 null mice and show that, in the central lobules, granule cells can be eradicated in the absence of Neurod1. Granule cells in the anterior lobules are partially viable and depend on as yet unknown genes, but the Purkinje cells show defects not previously recognized. Interestingly, delayed and incomplete Tg(Atoh1-cre) upregulation occurs in the most posterior lobules; this leads to near normal expression of Neurod1 with a concomitant normal differentiation of granule cells, Purkinje cells, and unipolar brush cells in lobules IX and X. Our analysis suggests that Neurod1 negatively regulates Atoh1 to ensure a rapid transition from proliferative precursors to differentiating neurons. Our data have implications for research on medulloblastoma, one of the most frequent brain tumors of children, as the results suggest that targeted overexpression of Neurod1 under Atoh1 promoter control may initiate the differentiation of these tumors.

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Acknowledgements

We express our thanks to Drs. K.-A. Nave and S. Goebbels, Max-Planck-Institute of Experimental Medicine, for providing the floxed Neurod1 mice used in this study. We also thank the Bioimaging Facility in the Department of Biology at University of Iowa for assisting with the Leica TCS SP5 confocal microscope. We are grateful to J. Kersigo for extensive help in breeding and genotyping and in the various steps during sample preparation and to K. Thompson for proofreading the manuscript.

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  1. Jacqueline E. Lee

    Present address: Geron Corporation, 230 Constitution Drive, Menlo Park, CA, 94025, USA

Authors and Affiliations

  1. Department of Biology, College of Liberal Arts and Sciences, University of Iowa, 143 BB, Iowa City, IA, 52242, USA

    Ning Pan, Israt Jahan & Bernd Fritzsch

  2. Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO, 80309, USA

    Ning Pan & Jacqueline E. Lee

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  1. Ning Pan
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  2. Israt Jahan
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Correspondence to Bernd Fritzsch.

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Ning Pan and Israt Jahan contributed equally to this paper.

This work was supported by an NIH grant (R01 DC 005590) to B.F.

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Pan, N., Jahan, I., Lee, J.E. et al. Defects in the cerebella of conditional Neurod1 null mice correlate with effective Tg(Atoh1-cre) recombination and granule cell requirements for Neurod1 for differentiation. Cell Tissue Res 337, 407–428 (2009). https://doi.org/10.1007/s00441-009-0826-6

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