title: Defects in the cerebella of conditional Neurod1 null mice correlate with effective Tg(Atoh1-cre) recombination and granule cell requirements for Neurod1 for differentiation.
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 beta-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.
authors.affiliation: Department of Biology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Pan
authors.forename: Israt
authors.initials: I
authors.lastname: Jahan
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Lee
authors.forename: Bernd
authors.initials: B
authors.lastname: Fritzsch
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism*; D001835:Body Weight; D002454:Cell Differentiation; D002531:Cerebellum / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005838:Genotype; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011689:Purkinje Cells / Q000378:metabolism; D011995:Recombination, Genetic
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; C500943:Atoh1 protein, mouse; C501008:Neurod1 protein, mouse