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Vol. LVIII, No. 16
August 11, 2006

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Where the Wnt Goes
NHGRI's Yang Explores The Making Of Skeletons

They are hugely important little dudes, those genes called Wnts. An amalgam of "wingless" and "int," the term Wnt derives from the first two members of the gene family to be discovered: wingless (Drosophila, or fruit fly) and int-1 (mouse). Wnts are signaling proteins that control many cell processes in a variety of different organisms, including mammals. They play crucial roles in early development, regulating cell proliferation, polarity, differentiation, migration and fate.

They are also implicated in disease. The most famous example is breast cancer, when Wnt genes, normally silent, are activated by a retrovirus.

Summer students participating in the 2006 Summer Residency Program got a full-court introduction to Wnts in Dr. Yingzi Yang's recent lecture, "The Making of Skeletons."

Dr. Yingzi Yang  
Yang studies cell-to-cell signaling in vertebrate limb development and skeletal morphogenesis. A fundamental aspect of developmental biology, morphogenesis concerns how the body's structures are generated, positioned, shaped and specialized.

As NHGRI's section head of developmental genetics, Yang concentrates on the Wnt and Hedgehog groups of signaling molecules. Her goal is to understand precisely how these signaling pathways act and interact with each other and with other signaling molecules in regulating vertebrate embryonic development. She spoke to her audience in Lipsett Amphitheater, where she offered a comprehensive overview of her work.

To understand pathological mechanisms, she told them, we must first understand normal biological processes. "However," she observed, "we cannot do experiments on human beings, so to gain insight into molecular pathways that govern embryological development we can study other vertebrate species and see results applied directly."

The mouse, Yang explained, is the only available mammalian model in which to do sophisticated genetic manipulation. She explained reverse genetics, covering the creation of knockout, knock-in and transgenic mice; and forward genetics, covering mutagenized mice treated with chemicals or DNA insertions.

She then laid out results of several experiments that showed how key aspects of skeletal development are controlled by Wnt signaling. She focused on Wnt action upon chondrocytes — cells that are cartilage-forming — and osteoblasts, the bone-forming cells. Both are manipulated by blocking or enhancing Wnt signaling.

Yang showed how, in skeletal morphogenesis, Wnt signaling is critical for later development. Receptors that are too active or inactive affect bone density. Too much can lead to osteoarthritis; too little, to osteoporosis.

In conclusion, she showed how Wnt signaling helps us understand the formation of healthy bone, cartilage and joint, with important implications for treatment.

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