Page 36 - Mouse Molecular Genetics

Full Abstracts
Program number is above title. Author in bold is the presenter.
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6
The (uro)chordate-specific
Gumby
gene governs angiogenesis and modulates Wnt signaling.
Elena Rivkin
1,2
,
Stephanie M
Almeida
1,2
,
Teresa A MacLean
1,2
,
Gang Xie
1
,
Sabine P Cordes
1,2
. 1)
Samuel Lunenfeld Research Institute, Toronto, Ontario,
Canada; 2) Department of Molecular Genetics, University of Toronto, 1 King’s Crescent, Toronto, ON Canada.
A complex interplay of signaling pathways regulates the sprouting of blood vessels from preexisting vasculature during
angiogenesis, and produces vessels uniquely adapted to organ physiology and function. Here we describe an angiogenic
phenotype in embryos homozygous for the mouse
gumby
mutation. We show that a point mutation in the novel (uro)chordate-
specific
Gumby
gene is responsible for this angiogenic phenotype. Furthermore we show that Gumby protein interacts with
Dishevelled 2 (Dvl2), a member of Wnt signaling pathways, and can stimulate canonical Wnt signaling in culture. In the mouse,
Gumby protein is localized to endothelial cells with active canonical Wnt signaling. Mutant gumby protein can still stimulate
canonical Wnt signaling in culture and canonical Wnt signaling is active in endothelial cells of
gumby/gumby
embryos, as
detected in TOPGAL reporter mice. However, expression of some known Wnt target genes is decreased
in
gumby/gumby
embryos. Because
Gumby
is deleted in patients manifesting mental retardation, craniofacial and cardiac deficits
of Cri du Chat Syndrome (CdCS), our findings for the first time suggest that Wnt signaling could be affected in CdCS. Thus,
understanding how Gumby acts to coordinate Wnt signaling in endothelial cells may provide broader insights into the cell
biology of CdCS.
7
Molecular pathogenesis of Joubert Syndrome and related disorders. Tamara Caspary
1
,
Holden Higginbotham
2
,
Laura E.
Mariani
1,3
,
Tae-Yeon Eom
2
,
Miao Sun
1
,
Vanessa L. Horner
1
,
Alyssa B. Long
1
,
Eva S. Anton
2
. 1)
Dept. of Human Genetics,
Emory University School of Medicine, Atlanta, GA; 2) The UNC Neuroscience Center, The University of North Carolina School
of Medicine, Chapel Hill, NC; 3) Graduate Program in Neuroscience, Emory University, Atlanta, GA.
Patients with Joubert Syndrome and related disorders (JSRD) suffer from a wide array of symptoms with variable clinical
presentation, including developmental delay, intellectual disability, abnormal respiratory rhythms, ataxia, oculomotor apraxia,
polydactyly, craniofacial defects, retinal dystrophy and nephronophthisis. The diagnosis of JSRD requires an MRI showing
the molar tooth sign. This hindbrain malformation arises from hypoplasia of the cerebellar vermis and thickened, elongated
superior cerebellar peduncles that fail to cross the midline. While JSRD is a rare, autosomal recessive, congenital disorder,
causative mutations for JSRD have been identified in the small GTPase,
ARL13B
,
the inositol phosphatase,
INPP5E
and 16
additional genes, all of which code for proteins related to primary cilia - thus, JSRD are members of the emerging class of
diseases known as ciliopathies. Primary cilia are essential for Sonic hedgehog (Shh) signaling, and we previously showed that
Shh signaling is regulated by Arl13b in mouse.
Here we investigate the pathogenesis of JSRD in mouse models using a conditional
Arl13b
allele and an ENU-
induced
Inpp5e
allele. We found Arl13b is critical for the localization of Inpp5e to cilia. Inpp5e loss misregulated Shh signaling
in a similar manner to Arl13b loss. Together these data are consistent with Inpp5e acting as a specific Arl13b effector. In order to
better understand the neurological defects in Joubert patients, we deleted
Arl13b
in specific cortical neurons or interneurons.
Defects in the placement or migration of these cells alter connectivity, which underlies the cognitive defects in a spectrum of
neurological disorders. In the absence of
Arl13b
,
we observed defects in the migration and placement of postmitotic interneurons
in the developing cerebral cortex. We found guidance cue receptors known to be important for interneuron migration normally
localize to interneuronal cilia, but their concentration and dynamics were abnormal in the absence of
Arl13b
.
Wild type Arl13b
rescued these defects whereas neither ARL13B variants from Joubert patients nor non-ciliary variants of Arl13b did. These data
suggest that defects in cilia-dependent interneuron migration underlie the neurological deficits in JSRD patients.
8
Genetic analysis of Down syndrome in mice.
Chunhong Liu
1
,
Masae Morishima
2
,
Li Zhang
1
,
Xiaoling Jiang
1
,
Kai Meng
1
,
Annie Pao
1
,
Michael Parmacek
3
,
Ping Ye
4
,
William Mobley
5
,
Allan Bradlley
6
,
Yuejin E. Yu
1*
. 1)
Genetics Program, Roswell
Park Cancer Institute, Buffalo, NY; 2) Department of Anatomy and Developmental Biology, Tokyo Women's Medical
University, Tokyo, Japan; 3) Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA; 4) School of Molecular
Bioscinces, Washington State University, Pullman, WA; 5) Department of Neuroscinces, University of California, San Diego, La
Jolla, CA; 6) Wellcome Trust Sanger Institute, Hixton, Cambridge, UK.
Trisomy 21, the most common live-born aneuploidy in humans, causes Down syndrome (DS). This genetic disorder is
associated with several major phenotypes, including heart defects, hematopoietic abnormalities, intellectual disabilities and
suppression of solid tumor growth. The mouse is a premier model organism for DS because the genomic regions on human
chromosome 21 are syntenically conserved with three regions in the mouse genome, located on mouse chromosomes 10, 16 and
17.
To expedite genetic analysis of DS, we have generated 12 mouse mutants with different genetic rearrangements in the human
chromosome 21 syntenic regions, using embryonic stem cell technology. Using these mutants, we have developed a complete
genetic model for DS, which is trisomic for all three human chromosome 21 orthologous regions. Generation and
characterization of the smaller chromosomal duplications and deletions have facilitated the establishment of the critical genomic
regions associated with the mutant phenotypes. These efforts should lead to the identification of the dosage-sensitive genes
underlying the phenotypes, which will serve as the entry point to the mechanistic details of the altered developmental processes.