Consequences of Aberrant Hedgehog Signaling During Zebrafish Development

Abstract

The Hedgehog signaling pathway is controlling proliferation, patterning and differentiation during development of vertebrates and invertebrates. Aberrant Hedgehog activity has been shown to be one of the underlying causes of a number of congenital disorders and multiple types of cancer. We investigated the consequences of an increased activity of Hedgehog signaling, by forward and reverse genetic approaches, using zebrafish as a model organism. We identified and characterized four mutants encoding Hip, Sufu, Patched1 and Patched2, all functioning as negative regulators of the Hedgehog pathway. Loss of function of these genes results in a slight activation of the Hedgehog pathway, leading to subtle morphological phenotypes. Zebrafish mutants for Patched1 and Patched2 were generated in an attempt to investigate the consequences of a constitutive activation of the pathway. These mutants show severe developmental defects, including an absence of the eyes, nose and pectoral fins and reduced pigmentation. Additionally, patched1/patched2 double mutants show a loss of blood circulation. Detailed analysis showed that a constitutive activation of the Hedgehog pathway induces ectopic formation of arteries at the expanse of venous formation.

The identified mutants assign novel and unexpected roles to the Hedgehog signaling pathway. Additionally, these mutants provide a unique model system, which will finally contribute to fully understand the role of Hedgehog signaling during development and disease.