Molecular middleman puts thyroid hormone in developmental signaling pathway

Tissues such as muscle and brain convert the inactive form of thyroid hormone, T4, into T3, the active form of thyroid hormone, when necessary. In the 1980s, researchers discovered that this conversion is accomplished by the deiodinase enzymes.

Several years ago, Antonio Bianco, Harvard Medical School associate professor of medicine at Brigham and Women’s Hospital, and colleagues discovered that the deiodinase D2 is regulated by the ubiquitination pathway. Postdoctoral fellow Monica Dentice found that the protein WSB1 was the D2 ligase, the molecular adapter that fits the ubiquitination machinery to the protein.

It is known that WSB1 is induced by the hedgehog proteins, a family studied by Cliff Tabin, HMS professor of genetics. Development balances between proliferation and differentiation, and the hedgehog family is known for accomplishing this feat. Yet there are gaps in understanding the process. For example, Indian hedgehog (Ihh) promotes proliferation in the bones of young embryos by turning on a hormone, PTHrP, but it was unclear how it accomplishes this.

The researchers thought WSB1 regulation of D2 and thyroid hormone activation might play a role. Working with Tabin’s lab, Dentice infected developing chick legs with a virus that overproduces Ihh, and she confirmed that D2 levels decreased in response to hedgehog’s command, and WSB1 and PTHrP levels increased.