The Barr Lab: Human Disease

Human
Disease

In the free-living nematode Caenorhabditis elegans, cilia are found on the dendritic endings ... More >

Sexual behaviors are evoked by a wide variety of sensory cues and generated by specialized sensory neurons ... More >

Several human genetic disorders, including autosomal dominant polycystic kidney disease ... More >

The molecular basis of human genetic diseases of cilia

References:

The C. elegans NPHP homologs function in the core (shared between the two sexes) and male-specific ciliated nervous systems. Shown here are abnormal cilia of nphp mutant worms (Andrew Jauregui).

Several human genetic disorders, including autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive PKD, Nephronophthisis (NPHP), Meckel-Gruber syndrome (MKS) and Bardet-Biedl Syndrome (BBS) share two common features: ciliary localized gene products and kidney cysts. Given that it is prohibitively difficult in humans to study the connection between ciliary protein function, localization, and disease, alternative experimental systems are necessary. In C. elegans it is feasible to study the roles of human disease gene homologs in cilia formation, morphogenesis, and signaling. The Barr laboratory has well-established C. elegans models for ADPKD and NPHP, and is currently developing a worm model for MKS, the leading syndromic cause of neural tube defects in humans. Results of our studies will broaden our understanding of how cilia develop, form, and function in normal and pathological states and provide new insight into the molecular basis of human ciliopathies.

For patients, the PKD Foundation is an excellent resource: http://www.pkdcure.org

Bae YK, Kim E, L’Hernault SW, and Barr, MM (2009). The CIL-1 PI 5-phosphatase localizes TRP Polycystins to cilia and activates sperm in C. elegans. Curr Biol. 19(19):1599-607.

Jauregui AR, Nguyen KC, Hall DH, Barr MM. (2008) The Caenorhabditis elegans nephrocystins act as global modifiers of cilium structure. J Cell Biol. 180(5):973-88.

Knobel KM, Peden EM, Barr MM. (2008) Distinct protein domains regulate ciliary targeting and function of C. elegans PKD-2. Exp Cell Res. 314(4):825-33.

Hu, J., Wittekind, S.G., and Barr, M.M. (2007) STAM and Hrs downregulate ciliary receptors and signaling in C. elegans. Molecular Biology of the Cell 18(9):3277-89.

Hu, J., Bae, Y.K., Knobel, K.M. and Barr, M.M. (2006) Regulation of ciliary sensory receptors by opposing activities of casein kinase II and calcineurin, Molecular Biology of the Cell 17:2200-11.

Barr, M.M., DeModena, J., Braun, D.,Nguyen, C.Q,. Hall, D.H. and Sternberg, P. (2001) The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway. Current Biology 11:1341-6.

Qin, H., Rosenbaum, J.S., and Barr, M.M. (2001) An ARPKD gene homologue is involved in Intraflagellar transport in C. elegans ciliated sensory neurons. Current Biology 11:457-461.

Barr, M.M. and Sternberg, P. (1999) A polycystic kidney-disease gene homologue required for male mating behaviour in Caenorhabditis elegans. Nature 401:386-389.

The C. elegans ADPKD gene battery is expressed in “B-type” male-specific sensory neurons. In the male tail, PKD-2::GFP localizes to sensory cilia and Pklp-6::DsRed2 labels sensory neurons (Erik Peden).