Rolf O. Karlstrom

esearch Interests: 

Developmental Neurobiology: Axon Guidance, Forebrain Patterning, and Pituitary Developement

My laboratory uses zebrafish as a simple vertebrate system to study how the forebrain and pituitary gland develop, and to investigate how axons are guided across the midline to form the forebrain commissures and optic chiasm. Accessible and rapid early development, combined with beautiful imaging characteristics and the ability to manipulate gene expression, make zebrafish a powerful model system for the study of early brain formation.

Pituitary Induction and Patterning

The vertebrate pituitary gland is the "master" endocrine gland and controls a wide range of metabolic functions, from growth, to reproduction, to stress responses. The zebrafish is a relatively untapped resource in the study of endocrine development, and has profound 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 (see time-lapse movie). Importantly, pituitary structure is highly conserved across vertebrate species, making studies in zebrafish directly relevant to human development.

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. In addition, aberrant Shh signaling in the adult pituitary is associated with common pituitary adenomas. A major project in the lab is to investigate the cellular and molecular mechanisms by which Shh regulates this endocrine gland, both in the embryo and post-embryonically. This research is aiding our understanding of human birth defects and is beginning to shed light on how mis-regulation of Shh signaling can lead to pituitary tumors.

Axon and Glial Guidance in the forebrain

We continue to use the zebrafish achiasmatic mutants as tools for investigating the mechanisms that guide axons across the midline of the forebrain. We recently showed that the belladonna (bel) mutation affects the lhx2 gene. In both lhx2 and shh mutants, the axon growth substrate is disrupted in specific ways, providing clues as to the axon 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 currently investigating how these glial cells find their correct positions in the forebrain and how they subsequently help establish of the optic chiasm and forebrain commissures.