Dataset Information

Sensory defects in Necdin deficient mice result from a loss of sensory neurons correlated within an increase of developmental programmed cell death.

ABSTRACT:

Background

The human NECDIN gene is involved in a neurodevelopmental disorder, Prader-Willi syndrome (PWS). Previously we reported a mouse Necdin knock-out model with similar defects to PWS patients. Despite the putative roles attributed to Necdin, mainly from in vitro studies, its in vivo function remains unclear. In this study, we investigate sensory-motor behaviour in Necdin deficient mice. We reveal cellular defects and analyse their cause.

Results

We report sensory differences in Necdin deficient mice compared to wild type animals. These differences led us to investigate sensory neuron development in Necdin deficient mouse embryos. First, we describe the expression pattern of Necdin in developing DRGs and report a reduction of one-third in specified sensory neurons in dorsal roots ganglia and show that this neuronal loss is achieved by E13.5, when DRGs sensory neurons are specified. In parallel, we observed an increase of 41% in neuronal apoptosis during the wave of naturally occurring cell death at E12.5. Since it is assumed that Necdin is a P75NTR interactor, we looked at the P75NTR-expressing cell population in Necdin knock-out embryos. Unexpectedly, Necdin loss of function has no effect on p75NTR expressing neurons suggesting no direct genetic interaction between Necdin and P75NTR in this context. Although we exclude a role of Necdin in axonal outgrowth from spinal sensory neurons in early developmental stages; such a role could occur later in neuronal differentiation. Finally we also exclude an anti-proliferative role of Necdin in developing sensory neurons.

Conclusion

Overall, our data show clearly that, in early development of the nervous system, Necdin is an anti-apoptotic or survival factor.

SUBMITTER: Andrieu D

PROVIDER: S-EPMC1687209 | biostudies-literature | 2006 Nov

REPOSITORIES: biostudies-literature

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Publications

Sensory defects in Necdin deficient mice result from a loss of sensory neurons correlated within an increase of developmental programmed cell death.

Andrieu David D Meziane Hamid H Marly Fabienne F Angelats Corinne C Fernandez Pierre-Alain PA Muscatelli Françoise F

BMC developmental biology 20061120

<h4>Background</h4>The human NECDIN gene is involved in a neurodevelopmental disorder, Prader-Willi syndrome (PWS). Previously we reported a mouse Necdin knock-out model with similar defects to PWS patients. Despite the putative roles attributed to Necdin, mainly from in vitro studies, its in vivo function remains unclear. In this study, we investigate sensory-motor behaviour in Necdin deficient mice. We reveal cellular defects and analyse their cause.<h4>Results</h4>We report sensory difference ...[more]

PMID: 17116257

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Project description:During differentiation, neurons experience a reorganization of DNA modification patterns within their genomes. However, the mechanisms underlying this developmental patterning and its role in defining the neuronaÂÂl state are currently unclear. Here, we find that the dÂÂe novo DNA methyltransferase Dnmt3a is necessary for elevated levels of 5-hydroxymethylcytosine (5hmC), a derivative of 5-methylcytosine (5mC), in olfactory sensory neurons (OSNs). Through an analysis of genome-wide 5mC and 5hmC distributions in isolated OSNs, we find that Dnmt3a-dependent 5mC and 5hmC occurs within regions of high accessibility, neural enhancers, and the transcription start sites of transcribed genes. Its loss results in the global disruption of gene expression patterns, including the upregulation of silent genes, the downregulation of mOSN-expressed genes, and the alteration of odorant-induced transcriptional responses of immediate early genes. Together, these results demonstrate that Dnmt3a is necessary to define the neuronal transcriptional state and may be broadly involved in refining expression profiles within differentiated cells. To determine the contributions of Dnmt3a to the DNA modification and transcriptional landscapes of a post-mitotic neuronal population, we performed DNA immunoprecipitation (DIP-seq) using antibodies specific for 5mC and 5hmC and rRNA-depleted transcriptional profiling (RNA-seq) coupled to high-throughput sequencing using genomic DNA or RNA from FACS-isolated mature olfactory sensory neurons (mOSNs) from main olfactory epithelium (MOE) of Dnmt3a wildtype (WT), heterozygous-null (Het), or homozygous-null (KO) 3-week old mice. Similarly, to compare this information with other epigenetic features of the MOE, we performed H3K4me1 (WT), H3K27ac (WT), and H3K27me3 (WT and KO) chromatin immunoprecipitation (ChIP)-seq and DNase I hypersensitivity assays (DNase-seq) using MOE nuclei from 3-week old mice. In addition, we assayed the influence of Dnmt3a-deficiency on the induction of odorant-responsive genes by exposing 3-week old Dnmt3a WT, Het, and KO mice to either water or a 1:1:1 mixture of amyl acetate:acetophenone:octanal for 1 hour and performed rRNA-depleted RNA-seq using RNA isolated from their MOEs.

Dataset Information

Sensory defects in Necdin deficient mice result from a loss of sensory neurons correlated within an increase of developmental programmed cell death.

Background

Results

Conclusion

Publications

Sensory defects in Necdin deficient mice result from a loss of sensory neurons correlated within an increase of developmental programmed cell death.

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