Research

Hedgehog Signaling in Mammalian Embryogenesis and Postnatal Physiology

We study the molecular mechanisms of Hedgehog (Hh) signaling in mammalian development and physiology, using mouse as a model system.   The Hh pathway plays a key role in many aspects of embryonic development, and dysregulation of Hh signaling is associated with human congenital anomalies and cancers.   A combination of mouse genetics (transgenic and knockout mice), cell biology and biochemistry is utilized to address three major issues:

• The molecular characterization of the Hedgehog signaling pathway

We currently investigate how the Hh ligand is produced, lipidated, and transported to generate a morphogen gradient, and the molecular mechanisms by which the Hh signal is transduced.   These studies serve as a paradigm for understanding lipid biology and vesicular trafficking in morphogen gradient formation, the involvement of cellular organelles, including the nucleus and the primary/motile cilia in receiving and interpreting the signal, and the evolution of developmental pathways.

• The role of Hedgehog signaling in various aspects of postnatal physiology and homeostasis such as stem cell maintenance and cancer formation

The postnatal roles of major signaling pathways remain poorly defined despite the widespread belief that they play a central role in postnatal development, physiology and homeostasis.   We are developing tools to address this fundamental question.

• Lung branching morphogenesis as a model system to study signal integration during mammalian embryogenesis

A major challenge in studying signaling pathways is to understand how multiple signals are integrated to make a tissue or organ.   We have chosen lung branching in mice as a model system for a number of reasons.   With the availability of organ culture, the stereotyped branching process and the ease of following the branching process, the lung is an attractive system to address the molecular mechanisms of branching morphogenesis, a process that involves epithelial-mesenchymal interactions and plays an essential role in the formation of many other organs.