Page 64 - Mouse Molecular Genetics

Full Abstracts
Program number is above title. Author in bold is the presenter.
progenitor populations in the head, we employed genetic tracing and cell ablation approaches. Surprisingly, the use of Myf5Cre
alleles in combination with the Cre-responsive ablator R26RDTA mouse line resulted in different phenotypic outputs in a
specific head muscle group, when compared to the loss of function of Myf5/Mrf4. Results will be discussed taking into account i)
the possibility of different cell progenitor populations for head muscles versus trunk muscles; ii) the specificity and strength of
Cre drivers and iii) the use of ubiquitous (ROSA26) versus lineage specific (Pax7nGFP/nlacZ) Cre-responsive reporters. More
generally, we will highlight the limitations of some commonly used genetic tools, and how this can impact on the biological
interpretation of gene deletions, genetic tracing, and cell ablation results. We also propose benchmarks for performing rigorous
studies with Cre-lox based mouse genetic tools. References: Gensch, N., Borchardt, T., Schneider, A., Riethmacher, D. and
Braun, T. (2008) 'Different autonomous myogenic cell populations revealed by ablation of Myf5-expressing cells during mouse
embryogenesis', Development 135(9): 1597-604. Haldar, M., Karan, G., Tvrdik, P. and Capecchi, M. R. (2008) 'Two cell
lineages, myf5 and myf5-independent, participate in mouse skeletal myogenesis', Dev Cell 14(3): 437-45. Sambasivan, R.,
Gayraud-Morel, B., Dumas, G., Cimper, C., Paisant, S., Kelly, R. G. and Tajbakhsh, S. (2009) 'Distinct regulatory cascades
govern extraocular and pharyngeal arch muscle progenitor cell fates', Dev Cell 16(6): 810-21.
Genome-wide mapping of gene-microbiota interactions in susceptibility to autoimmune skin blistering. Girish Srinivas
Steffen Möller
Sven Künzel
Jun Wang
Detlef Zillikens
John Baines
Saleh Ibrahim
. 1)
Max Planck Institute for
Evolutionary Biology, Plön, Germany; 2) Department of Dermatology, University of Lübeck, Lübeck, Germany; 3) Institute for
Experimental Medicine, University of Kiel, Kiel, Germany; 4) These authors contributed equally to this work.
Susceptibility to chronic inflammatory diseases is determined by the interaction of immunogenetic and environmental risk
factors. In particular, resident microbial communities as environmental factors are the subject of intense scrutiny due to numerous
observations of differences between healthy and diseased states. However, whether differences in community composition or
structure are of primary etiological importance or secondary to the altered inflammatory environment remains largely unknown.
Here we provide direct experimental evidence for host gene-microbiota interactions contributing to disease risk in a mouse model
of epidermolysis bullosa acquisita (EBA), a chronic autoantibody-induced inflammatory disease afflicting the skin. By using an
advanced intercross population, we simultaneously identified genetic loci contributing to variability in the skin microbiota,
susceptibility to autoimmune skin blistering and their overlap. Furthermore, treating the abundances of individual bacterial
species as covariates with disease lead to the discovery of novel disease loci. Specifically, a reduction in the abundance of
numerous individual species is associated with increased disease risk. This demonstrates a primary role for resident microbes in
disease etiology and underscores the importance of the skin microbiota in protection from disease. We anticipate our results to
further motivate the identification and characterization of individual beneficial members of host-associated microbial
communities and their interactions, in particular with respect to their potential for immunomodulatory drug development.
The chromatin remodeler Chd5 modulates neuronal morphology and behavior. Assaf Vestin
Guy Horev
Wangzhi Li
Alea Mills
. 1)
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY; 2) Stony Brook University, Stony Brook, NY.
Chd5 is a predicted chromatin remodeling protein of the SWI/SNF superfamily that is robustly expressed in neuronal tissues
such as the brain. Our laboratory previously identified
as a tumor suppressor mapping to human 1p36, a region of the
genome that is frequently deleted in neuronal malignancies. Although a number of chromatin remodeling proteins have been
shown to modulate brain function, whether Chd5 performs a similar role is unknown. Here we show that Chd5 plays a
fundamental role in the brain. Chd5 expression initiates in differentiating neurons during embryogenesis and is maintained in
post-mitotic neurons in the adult. Chd5-compromised mice are viable and have unique behavioral phenotypes such as
hyperactivity and repetitive behaviors. In addition, analysis of Chd5-compromised brain indicates that cortical and CA1
hippocampal neurons have abnormal dendritic morphology. These findings reveal a role for Chd5 in neuronal function in vivo
and will help to elucidate how regulation of chromatin, and in turn regulation of gene expression, affects brain function.
Patterns of recurrent and tissue-specific copy number variants in the mouse genome. Andrea E. Wishart
M. Elizabeth O.
Susan T. Eitutis
Kathleen A. Hill
. 1)
Department of Biology, The University of Western Ontario, London, Ontario,
Canada; 2) Department of Computer Science, The University of Western Ontario, London, Ontario, Canada.
Identifying regions of recurrent copy number variants (CNVs) gives insight into the mechanisms by which CNVs are formed in
the mammalian genome, as well as into the potential for functional impact on the expression of genes in and around these
regions. Here, we apply the Mouse Diversity Genotyping Array (MDGA), a high-resolution array available for mice querying
approximately 530 000 highly reliable SNP positions to detect copy number across autosomes. Genomic DNA was isolated from
tissue samples taken from related mice on a mixed C57BL/6J and CBA/CaJ background: spleen and cerebellum of two
prematurely aged
brothers and two wild-type (WT) brothers, cerebellum only of two additional
brothers, and
one repetition of each tissue from one WT mouse. Additionally, spleen and cerebellum from one C57BL/6J inbred mouse was
included for a total of 14 samples. CNV calls were made using a Hidden Markov Model within Partek Genomics Suite using
stringent parameters, and then filtered to exclude regions called with a low marker density. Using custom tracks in the UCSC
Genome Browser constructed from published CNV datasets, we identified CNV regions previously detected in a publicly
available 351-mouse MDGA dataset, as well as variants unique to our samples. Of the 62 CNV events called, none were detected