Chapter 229 - Hedgehog Signaling in Development and Disease

Abstract

The hedgehog (Hh) signaling pathway gives cells information that they need to make the embryo develop properly. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. When the pathway malfunctions, it can result in diseases like basal cell carcinoma. Hh plays a vital role in the development of multiple organ systems in the fly and vertebrates. Hh proteins are synthesized as precursor proteins of about 45 kD. Studies of the normal functions for the Hhs in animal models have helped in the understanding of Hh-related diseases. Many studies have shown that sonic Hh (Shh) acts as a morphogen in the nervous system, where it is secreted from the notochord and later from the floor plate, patterning neurons along the dorsoventral axis of the neural tube in a dose-dependent manner. The patterning functions of Hh are also highlighted in humans where mutations have clearly been linked to developmental disorders, including spina bifida, neural tube defects, and skeletal deformations. In addition to tumors where mutations in components of the Hh pathway lead to its activation, Hh ligand-driven pathway activation has more recently been implicated in a large number of cancers, such as small cell lung cancer, various types of upper GI tract tumors such as pancreatic ductal adenocarcinoma, prostate cancer, and, more recently, multiple myeloma or other B cell derived malignancies.