All Projects

Our analysis of zebrafish forebrain mutants led to the discovery that the small protein Sonic Hedgehog (Shh) is a critical player in the early induction of the pituitary placode, as well as in the differentiation of a subset of endocrine cell types. This role for Shh is conserved across vertebrates, with defects in human Shh signaling leading to congenital disorders affecting pituitary development. This research is contributing to our understanding of human birth defects affecting ventral forebrain and pituitary formation.

The vertebrate pituitary gland is the "master" endocrine gland and controls a wide range of metabolic functions including growth, reproduction, and stress responses. The zebrafish is a relatively untapped resource in the study of endocrine development, and has major advantages for research into pituitary development. In particular, the genetic and optical accessibility of the embryo makes it possible to observe and manipulate the earliest events in pituitary formation. Importantly, pituitary structure is highly conserved across vertebrate species, making studies in zebrafish directly relevant to human development.

The regulation of tissue growth is critically important during embryonic and post-embryonic development across species, and adult tissues must continually be renewed through the tightly regulated proliferation of stem cell populations. In zebrafish, the ventral forebrain and pituitary continue to grow throughout life, making it an excellent system to study the mechanisms that regulate stem cell growth and renewal. We are studying how the cell-cell signaling molecule Sonic Hedgehog regulates cell proliferation during the massive growth phase that occurs during larval development. We have evidence that Shh signaling acts on adult hypothalamic and pituitary stem cells, similar to its role in regulating other neural stem cells. Misregulation of Shh signaling in the adult is associated with human pituitary adenomas, and our studies thus promise to shed light on the mechanisms underlying these common tumors.

Our new transgenic tools have allowed us to monitor the ontogeny of endocrine function both under normal conditions, and when an embryo experiences embryonic stressors as can occur in complicated human pregnancies. We have begun to examine the effects of altered thyroid hormone levels on thyrotrope development and the establishment of negative feedback regulation within the Hypothalamic pituitary thyroid (HPT) axis. We are also examining how Hh signaling may affect pituitary function, and the consequences this may have on the endocrine regulation of osmotic balance. These new studies are bringing the power of zebrafish genetics and transgenics to the study of endocrine physiology.

A large number of zebrafish retinotectal mutants, in which axons from the eye fail to reach their proper targets in the brain, are important tools for investigating the mechanisms that guide axons across in the developing brain. We showed that the “achiasmatic” mutant belladonna (bel) affects the lhx2 gene and that in both lhx2 and shh mutants the axon growth substrate is disrupted in specific ways. This analysis is providing clues as to the guidance mechanisms that are required for proper midline crossing. In particular, we have characterized a unique population of glial cells that spans the midline just prior to axon crossing, and shown that this glial bridge is disrupted in the achiasmatic mutants. We are now interested in understanding how these glial cells find their correct positions in the forebrain and how they subsequently help establish of the optic chiasm and forebrain commissures.