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

Ning Pan; Israt Jahan; Jacqueline E Lee; Bernd Fritzsch

doi:10.1007/s00441-009-0826-6

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

Ning Pan, Israt Jahan, Jacqueline E Lee and Bernd Fritzsch

Cell and tissue research, Vol.337(3), pp.407-428

09/2009

DOI: 10.1007/s00441-009-0826-6

PMCID: PMC3023111

PMID: 19609565

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Abstract

Neurod1\nis a crucial basic helix-loop-helix gene for most cerebellar granule cells and mediates the differentiation of these cells downstream of\nAtoh1\n-mediated proliferation of the precursors. In\nNeurod1\nnull mice, granule cells die throughout the posterior two thirds of the cerebellar cortex during development. However,\nNeurod1\nis also necessary for pancreatic β-cell development, and therefore\nNeurod1\nnull mice are diabetic, which potentially influences cerebellar defects. Here, we report a new\nNeurod1\nconditional knock-out mouse model created by using a\nTg(Atoh1-cre)\nline to eliminate\nNeurod1\nin the cerebellar granule cell precursors. Our data confirm and extend previous work on systemic\nNeurod1\nnull mice and show that, in the central lobules, granule cells can be eradicated in the absence of\nNeurod1\n. 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\nTg(Atoh1-cre)\nupregulation occurs in the most posterior lobules; this leads to near normal expression of\nNeurod1\nwith a concomitant normal differentiation of granule cells, Purkinje cells, and unipolar brush cells in lobules IX and X. Our analysis suggests that\nNeurod1\nnegatively regulates\nAtoh1\nto 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\nNeurod1\nunder\nAtoh1\npromoter control may initiate the differentiation of these tumors.

Cerebellum

Granule cell development

Mouse (Neurod1 null)

bHLH genes

Cell death

Proliferation regulation

Details

Title: Subtitle: Defects in the cerebella of conditional Neurod1 null mice correlate with effective Tg(Atoh1-cre) recombination and granule cell requirements for Neurod1 for differentiation
Creators: Ning Pan - Department of Biology, College of Liberal Arts and Sciences, University of Iowa, 143 BB, Iowa City, IA 52242, USA; Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA
Israt Jahan - Department of Biology, College of Liberal Arts and Sciences, University of Iowa, 143 BB, Iowa City, IA 52242, USA
Jacqueline E Lee - Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA
Bernd Fritzsch - Department of Biology, College of Liberal Arts and Sciences, University of Iowa, 143 BB, Iowa City, IA 52242, USA
Resource Type: Journal article
Publication Details: Cell and tissue research, Vol.337(3), pp.407-428
DOI: 10.1007/s00441-009-0826-6
PMID: 19609565
PMCID: PMC3023111
NLM abbreviation: Cell Tissue Res
ISSN: 0302-766X
eISSN: 1432-0878
Language: English
Date published: 09/2009
Academic Unit: Iowa Neuroscience Institute; Biology; Craniofacial Anomalies Research Center
Record Identifier: 9984070821702771

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