S06-04 Molecular and developmental insights into the pathogenesis of the SOX9Y440X campomelic dysplasia mutation

MECHANISMS OF DEVELOPMENT

S31

1 2 6 ( 2 0 0 9 ) S 3 0 –S 3 1

these, full-of-fluid, to encode a novel predicted secreted protein

S06-04

that is expressed in the somitic mesoderm along the migration

Molecular and developmental insights into the pathogenesis of

pathway of lymphangioblasts, the earliest precursors of the

the SOX9Y440X campomelic dysplasia mutation

lymphatic system. Using a series of new transgenic lines to visu-

Kathryn S.E. Cheah1,2, Tiffany Au1, Irene Y.Y. Szeto1,

alize, at single cell resolution, the vasculature of full-of-fluid

Sarah Wynn1, Y.S. Chan3, Kenneth Cheung4,2, Wood Yee Chan5,

mutants as well as vegfc deficient embryos, we found that both

Robin Lovell-Badge6, Danny Chan1,2, Bernd Fritzsch7

the loss of full-of-fluid or Vegfc-Ft4 signaling leads to a failure of

1

all lymphangiogenesis and hemangiogenesis from the posterior cardinal vein.Significantly, we have recently identified a human patient population that develops, among other phenotypic characteristics, lymphedema and demonstrate here that these patients have molecular lesions in the human orthologue of the full-of-fluid gene. Data from the human clinic and the ability to experimentally address the mechanism-of-action of the full-offluid

gene

provides

new

insights

into

early

vertebrate

lymphangio-genesis.

Department of Biochemistry, The University of Hong Kong, Hong Kong,

China 2

Centre for Reproduction, Development & Growth, The University of

Hong Kong, Hong Kong, China 3

Department of Physiology, The University of Hong Kong, Hong Kong,

China 4

Department of Orthopaedic Surgery, The University of Hong Kong,

Hong Kong, China 5

Department of Anatomy, Chinese University of Hong Kong, Hong

Kong,China 6

doi:10.1016/j.mod.2009.06.1055

Division of Developmental Genetics, MRC National Institute for Medical

Research, London, UK 7

Department of Biological Sciences, University of Iowa, Iowa City, USA

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Human SOX9 mutations cause the skeletal malformation syn-

Judging a book by its cover: How facial morphology a may predict

drome campomelic dysplasia (CD). Complete inactivation of the

underlying molecular pathology

Sox9 gene in mice results in failure of cartilage formation. Studies

Jill Helms

in zebrafish and Xenopus suggest that Sox9 may be crucial for

Stanford University, CA, United States Strong evolutionary forces have fixed the pattern of the face, yet different species can stretch and mold it to a remarkable degree. The same cadre of genes that establish the ‘‘bauplan’’ of the face are also candidates for pathological conditions. In my laboratory we use a variety of animal models (mice, chicks, quails, ducks, pigeons) and approaches (genetic, biochemical, and experimental manipulation) to understand how the face is patterned. These approaches have revealed the roles that the cranial neural crest and surface ectoderm play in establishing species-specific facial morphology, and have allowed us to identify some of the key transcriptional regulators that control speciesspecific facial morphology. Two pathways in particular have proven to be tremendously important: Wnt signaling mediates maxillary outgrowth, how perturbations in Wnt signaling lead to facial clefting, and Hedgehog signaling controls mediolateral growth of the face. In this symposium I will discuss our recent work on Sonic hedgehog signaling in the face. We show that disruptions in Hedgehog pathway activity are responsible for a spectrum of facial anomalies ranging from the well-known phenotype of cyclopia, to facial duplications and the rare condition of diprosopus. Collectively, these data support the antediluvian theory of ‘‘Cosmobia’’, espoused by Wilder in 1908, which suggests that symmetrical forms of facial dysmorphology represent a continuum, and which we now show are attributable to disruptions in a single molecular pathway. doi:10.1016/j.mod.2009.06.1056

specification of the otic placode. In mice, loss of Sox9 results in failure of otic placode invagination. Heterozygous mutations in human SOX9 result in conductive and sensorineural deafness in some CD patients, implying a later morphogenetic role but phenotypic details are limited. Sox9

=

null mice die before morpho-

genesis of the inner ear is complete, precluding investigation of the role of Sox9 later in ear development. Because all the SOX9 mutations are heterozygous and appear to cause loss of function, the CD phenotype has been attributed to haploinsufficency of SOX9. However SOX9 proteins containing an intact HMG box and a truncated activation domain may act dominant negatively by competition with the wild-type for binding to target genes and interfere with interaction with partner factors via the transactivation domain. To assess whether such mutations in SOX9 may act via a dominant interference mechanism we generated transgenic and conditional knock’in mice expressing a mouse equivalent of a CD mutation, a Y440X nonsense mutation causing premature termination within the trans-activation domain of SOX9 (Sox9Y440X). We compared the phenotypic impact of the Sox9Y440X mutation with a Sox9 null mutation. These studies point to an essential role for Sox9 in inner ear and intervertebral disc development and context dependent mechanisms for the Y440X nonsense mutation. doi:10.1016/j.mod.2009.06.1090