Page 67 - Mouse Molecular Genetics

Full Abstracts
Program number is above title. Author in bold is the presenter.
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95
Investigation of hippocampal dendritic complexity in a potential XLMR mouse model. C. Y. Chen
1*
,
M. S. Tsai
1
,
C. Y.
Lin
1
,
I. S. Yu
1
,
Y. C. Hsu
1
,
C. Y. Kao
1
,
S. W. Lin
1
,
L. J. Lee
2,3
. 1)
Department of Clinical Laboratory Sciences and Medical
Biotechnology National Taiwan University; 2) Graduate Institute of Anatomy and Cell Biology National Taiwan University; 3)
Graduate Institute of Brain and Mind Sciences National Taiwan University.
Early deletion of Cul4b, encoding a scaffold protein of the E3 ubiquitin ligase complex and responsible for X-linked mental
retardation (XLMR), causes prenatal lethality in mice that has frustrated attempts to characterize the phenotypes in vivo. Here,
we generated Cul4b conditional knock-out mice and successfully rescued Cul4b mutant mice by deleted Cul4b in epiblast stage
using Sox2-Cre transgenic mice. The structure and organization of the cortex, striatum, and hippocampus in Cul4b/Y mice
showed no difference. The CUL4B expression in hippocampus was dominant in CA1 and CA3 region. Because the memory
circuit is highly related with CA1 pyramidal cells, the apical and basilar dendrites of CA1 pyramidal cells were examined by
Golgi impregnation. Although the number of intersections between the dendritic arbors was comparable in Cul4b/Y and
Cul4blox/Y mice, the number of segments in apical dendrites was significantly reduced in Cul4b/Y mice. Moreover, we found
that deletion of Cul4b lead to increased epileptic susceptibility and spatial learning deficits. Our results suggested Cul4b/Y mice
may be as a potential XLMR model that is further valuable for the development of a therapeutic strategy of MR.
96
Maged1 deficiency results in increased anxiety-like behaviors, disturbed sexual behaviors and late onset obesity
associated with reduced levels of hypothalamic oxytocin.
Carlos Dombret
1
,
Tuan Nguyen
1
,
Mathieu Bertrand
2
,
Jacques
Michaud
3
,
Hélène Hardin-Pouzet
4
,
Olivier Schakman
5
,
Olivier RY De Backer
1
. 1)
URPHYM, NARILIS, FUNDP school of
Medicine, University of Namur,5000 Namur, Belgium; 2) Molecular Signaling and Cell Death Unit, Department for Molecular
Biomedical Research, VIB, 9052 Ghent, Belgium; 3) Université de Montréal, Sainte-Justine Hospital Research Centre, Montréal
H3T1C5, Canada; 4) UPMC - Paris 6 University, PMSNC lab, CNRS UMR 7224, INSERM UMRS 952, 75005 Paris, France; 5)
Laboratory of Cell Physiology, Institute of Neuroscience IoNS, Université Catholique de Louvain, Brussels B-1200, Belgium.
MAGED1 is a member of the MAGE gene family that also includes NECDIN and MAGEL2, two genes defective in patients
with the neurobehavioural Prader-Willi Syndrome. Oxytocin is produced by hypothalamic neurons and can act as a
neurotransmitter that promotes social behaviors such as social exploration and recognition, pair bonding and parental care.
Growing evidences indicate that oxytocin could be involved in autism spectrum disorders. It has been shown previously that, in
mice, Maged1 regulates developmental neuron apoptosis and circadian activity. Here we show that Maged1-deficient mice
develop progressive obesity associated with hyperphagia and reduced motor activity. Loss of Maged1 also results in a behavioral
syndrome that associates impairment in social interactions, increased anxiety-like behaviors, and infertility of the males caused
by a lack of sexual interest. These behavioral traits, which evocate autistic symptoms in humans, are associated with a severe
reduction of brain oxytocin level. These observations show that Maged1 plays important and pleiotropic functions in the control
of social and sexual behaviors, motor activity and energy balance.
97
The role of Keratin 76 in epidermal homeostasis and barrier function maintenance. Tia M. DiTommaso
1
,
Helen Pearson
2
,
Holger Schluter
2
,
Pritinder Kaur
2
,
Patrick Humbert
2
,
Ian Smyth
1,3
. 1)
Biochemistry & Molecular Biology, Monash University,
Melbourne, Australia; 2) The Peter MacCallum Cancer Institute, Melbourne, Australia; 3) Department of Anatomy and
Developmental Biology, Monash University, Melbourne, Australia.
In collaboration with the Wellcome Trust Sanger Institute, we have implemented a rigorous reverse genetic screen in mice to
identify genes involved in the development and maintenance of the epidermis. The Keratin76 (Krt76) gene is a prime example of
new insights into the biology of the skin that have been identified as a result of this screen. The phenotype of the Krt76
knockouts
(
Krt76
tm1a/tm1a
)
includes hyperpigmentation, hyperkeratosis as well as defects in homeostasis and differentiation.
Transepidermal water loss (TEWL) assays indicate that the epidermal barrier is affected, although the layered organization of the
epidermis appears to be normal. Furthermore, loss of Krt76 leads to a significant decrease in lifespan with no mice surviving
beyond 12 weeks of age. Lifespan can be significantly increased in the
Krt76
tm1a/tm1a
mice with the administration of a broad
spectrum antibiotic, although this appears to only prolong lifespan by 5-6 weeks. Taken together, these data suggest that a tight
junction specific barrier function defect leads to dehydration, bacterial infection, and subsequent lethal epidermal pathology.
Closer inspection into the organization of the epidermis with an anti-claudin 1 antibody, a tight junction specific marker, has
revealed mislocalization of claudin-1 in
Krt76
tm1a/tm1a
mice as compared to wild type littermates. The functionality of the tight
junction complexes in these mice is being further investigated by comparing the diffusion of a subcutaneously injected biotin
tracer toward the skin surface. Our data indicate that the Krt76 knockout mouse may provide insight into the role of intermediate
filaments in the molecular architecture and stability of tight junction complexes in mammalian stratified epithelia. Our model
may support other emerging research to identify roles of intermediate filaments outside of mechanical and structural
cytoprotection. This study highlights an approach to characterize gene expression by targeted mutagenesis, but also furthers the
investigation of cell biology using the skin as model system.
98
BXD mouse lines as a genetic reference population for the metabolic syndrome.
Evan Williams
1
,
Pénélope Andreux
1
,
Charles Thomas
2
,
Raphael Doenlen
2
,
Philippe Cettour-Rose
2
,
Xavier Warot
2
,
Robert W. Williams
3
,
Johan Auwerx
1
. 1)