Developmental Genes and Human Disease - Carol Wicking

A/Prof Carol Wicking

Defects arising from abnormal embryonic development are a major cause of infant mortality and childhood disability. Many such disorders are characterised by anomalies of the limbs and craniofacial region, suggesting a conservation of the molecular development of these structures. We are investigating the molecular aspects of limb and face development with a particular focus on the role of the hedgehog signalling pathway in these processes.

We primarily use the mouse as a model system and have conditionally deleted the hedgehog receptor patched in the limb and face at varying stages of development. In the limb this has led to patterning defects as well as uncovering a novel role in the very earliest stages of skeletal development. We have completed the analysis of the patterning defects, thus contributing to our understanding of how digit number and identify are determined. These studies are important because the limb has long been considered a paradigm for organogenesis, and findings in this system can often be extrapolated to other organs.

Over the past several years the primary cilium has emerged as a novel cellular compartment required for hedgehog signalling. The primary cilium is a single non-motile microtubule-based organelle that protrudes from the surface of virtually every vertebrate cell. Aberrant formation of the cilium leads to a range of human disorders known as ciliopathies, and studies in mice have revealed a firm link between cilia and hedgehog signalling. In collaboration with Emma Whitelaw at QIMR we have identified a mouse with an N-ethyl-N-nitrosourea (ENU) induced point mutation in a cilia-related gene. Analysis of this mouse is yielding valuable insight into the role of the primary cilium in hedgehog signalling and disease.

Research Projects

• Conditional knockout of the hedgehog receptor patched in the developing mouse limb causes novel patterning defects


• Investigating the role of patched in development of the face through mouse knockout studies


• Identification and analysis of genes regulated by the transcription factor Gli3 in the developing limb


• A novel role for hedgehog signalling in the very early stages of chondrogenesis in the limb


• Using an ENU-induced mutation in the mouse to investigate the role of the primary cilium in hedgehog signalling and disease

Key Publications

Butterfield, N.C., Metzis, V., McGlinn, E., Bruce, S.J., Wainwright, B.J., and Wicking, C. (2009). Patched1 is a crucial determinant of asymmetry and digit number in the vertebrate limb. Development 136: 3515-3524.

Town, L., McGlinn, E., Fiorenza, S., Metzis, V., Butterfield, N.C., Richman, J.M., and Wicking, C., (2009). The metalloendopeptidase gene Pitrm1 is regulated by hedgehog signalling in the developing mouse limb and is expressed in muscle progenitors. Developmental Dynamics 238: 3175-3184.

Buchtova, M., Handrigan, G.R., Tucker, A.S., Lozanoff, S., Town, L., Fu, K., Diewert, V.M., Wicking, C., and Richman, J.M. (2008). Initiation and patterning of the snake dental lamina are dependent on Sonic Hedgehog signalling. Developmental Biology 319: 132-145.

McGlinn, E., Richman, J.M., Metzis, V., Town, L., Butterfield, N.C., Wainwright, B.J., and Wicking, C. (2008). Expression of the NET family member Zfp503 is regulated by hedgehog and BMP signaling in the limb. Developmental Dynamics 237: 1172-1182.

Bennetts, J.S., Rendtorff, N.D., Simpson, F., Tranebjaerg, L., and Wicking, C. (2007). The coding region of TP53INP2, a gene expressed in the developing nervous system, is not altered in a family with autosomal recessive non-progressive infantile ataxia on chromosome 20q11-q13. Developmental Dynamics 236: 843-852.

Simpson, F., Lammerts van Bueren, K., Butterfield, N., Bennetts, J.S., Bowles, J., Adolphe, C., Simms, L.A., Young, J., Walsh, M.D., Leggett, B., Fowles, L.F., and Wicking, C. (2006). The PCNA-associated factor KIAA0101/p15PAF binds the potential tumour suppressor product p33ING1b. Experimental Cell Research 312: 73-85.

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