Abstracts - Society for Developmental Biology

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however, and its role in CSF maintenance is unknown. Future research will focus on definitively establishing the role of
I11 in hydrocephalus and dissecting its normal function.
Program/Abstract # 421
The Bardet-Biedl syndrome modifier CCDC28B participates in ciliogenesis and modulates mTORC2 function
Cardenas, Magdalena, Institut Pasteur de Montevideo, Montevideo, Uruguay; Osborn, Daniel P.S. (Institute of Child
Health, University College London, London, United Kingdom); Irigoín, Florencia; Gascue, Cecilia (Institut Pasteur de
Montevideo, Montevideo, Uruguay); Katsanis, Nicholas (Center for Human Disease Modeling, Duke University, Durham,
NC, United States); Beales, Philip L. (Institute of Child Health, University College London, London, United Kingdom);
Badano, José L. (Institut Pasteur de Montevideo, Montevideo, Uruguay)
Bardet-Biedlsyndrome is a rare genetic disorder characterized by retinal degeneration, obesity, learning difficulties,
polydactyly and malformations of the gonads and kidneys. To date, sixteen BBS genes have been identified (BBS1-12,
MKS1, CEP290, FRITZ/C2ORF86, SDCCAG8) and their encoded proteins have been shown to participate in different
aspects of the biology of ciliaincluding cilia formation/maintenance and modulating cilia-dependent signaltransduction,
findings that have prompted the classification of BBS as aciliopathy. Although historically considered an example of
Mendelian trait, the identification and mutational screening of different BBS genes has demonstrated that in some families
at least, mutations at more than one bona fide BBS locus or second site modifiers segregate with the disease and modulate
its penetrance and expressivity. CCDC28B (MGC1203) is a second site modifier of BBS encoding a protein of unknown
function. Here we report the first functional characterization of this protein and show that it affects ciliogenesis in zebrafish
and consequently causes a number of phenotypes that are characteristic of cilia dysfunction including hydrocephalus, leftright
axis determination defects and renal impairment. Furthermore, we show that CCDC28B interacts with SIN1, a
structural member of the mTOR complex 2 (mTORC2), and modulates its activity both in vitro and in vivo. Importantly,
the mTOR pathwayhas been associated recently to the cilium whereby both cilia are required for the correct regulation of
the pathway and mTOR participates in ciliogenesis.Therefore, our results shed light into the biological function of the
BBSsecond site modifier CCDC28B, providing novel insight to understand the pathogenesis of this human condition, and
potentially implicates mTORC2 signaling in the organization of cilia.
Program/Abstract # 422
Dosage effect of Six3 in the pathogenesis of holoprosencephaly
Geng, Xin; Oliver, Guillermo, St. Jude Children's Research Hospital, Memphis, United States
Holoprosencephaly (HPE) is the most common forebrain malformation. It is defined as the incomplete separation of the
two cerebral hemispheres. Based on the severity of the defect, HPE is divided into three forms, alobar, semi-lobar and
lobar. The pathology of HPE is variable, even within families carrying the same mutation. The cause(s) of this variability
remains unknown. Here we demonstrate that variability in Six3 dosages will lead to different forms of HPE. The semilobar
HPE phenotype is the result of a severe down-regulation of Shh expression in the midline of the ventral forebrain.
Consistent with this conclusion, elevation of the Shh signaling activity by deleting one allele of Ptch1 fully rescued the
semi-lobar HPE phenotype. This study is the first study to show that different forms of HPE can originate from variations
in the dosage of a transcription factor and provides a possible explanation for the variable pathology of HPE.
Program/Abstract # 423
Identification of predominant pattern of co-regulation among kinetochore genes
Erliandri, Indri; Reinhold, William (National Cancer Institute, Bethesda, United States); Liu, Hongfang (Lombardi
Cancer Centre, Washington, United States); Zopilli, Gabrielle (Department of Internal Medicine, Genoa, Italy); Pommier,
Yves; Larionov, Vladimir (National Cancer Institute, Bethesda, United States)
The NCI-60 cell line panelis the most extensively characterized set of cells in existence. It provides multiple forms of data
on different cancertypes, and has been used extensively as a screening tool for drug discovery. Previously, the potential of
this panel has not been applied to the fundamental cellular processes of chromosome segregation. In the current study, we
used data from multiple microarray platforms accumulated for the NCI-60 to characterize an expression pattern of genes
involved in kinetochore assembly. This analysis revealed that 17 genes encoding the constitutive centromere associated
network of the kinetochore core (the CCAN complex) plus four additional genes with established importance in
kinetochore maintenance (CENPE, CENPF, INCENP, and MIS12) exhibit similar patterns of expression in the NCI-60,
suggesting a mechanism for co-regulated transcription of these genes which is maintained despite the multiple genetic and
epigenetic rearrangements accumulated in these cells. Multiple potential regulatory influences are identified for these
genes, including transcription factors, DNA copy number, and microRNAs. In addition, alterations of expression levels of
these genes are associated with karyotypic complexity. Thus, our results provide a prerequisite for experimental studies on