00:00

Rolf Karlstrom

One of the great challenges of our time is to understand how the most complex tissue in the universe, the human brain, can arise from a single cell, the fertilized egg. My lab’s research is focused on one aspect of this problem, understanding the molecular and cellular mechanisms that guide formation of the ventral forebrain during embryonic development. This includes investigation into the cell-cell signaling mechanisms that induce embryonic cells to acquire unique neural and endocrine fates (cell differentiation), how these signals control tissue growth (cell proliferation), as well as how cells interact to establish proper functionality in the brain and pituitary gland.

I first got hooked on the question of how the nervous system gets “wired” in an insect (grasshopper) embryo, a project I pursued during my Ph.D. in the Lab of Dr. Michael Bastiani at the University of Utah. I then moved to a postdoctoral fellowship in the lab of Dr. Friedrich Bonhoeffer were we attempted to identify all of the genes needed to form the neural connections between the eye and brain, using the zebrafish as a genetically accessible model organism. In collaboration with the Nusslein-Volhard lab, we identified over 35 genes required for the formation of this retinotectal projection (Karlstrom et al., 1996, 1997). A subsequent postdoctoral fellowship in the lab of Dr. Alex Schier resulted in the identification of the genes responsible for one of these axon guidance mutants (Karlstrom et al., 1999), and set me on the path of studying the role hedgehog mediated cell-cell signaling in forebrain development and axon guidance.

Since establishing my research lab at UMass in 1999 I have contributed to our understanding of the molecular and cellular mechanisms that guide early development of the ventral vertebrate forebrain.  We have subsequently cloned 3 more of the achiasmatic mutants (Karlstrom et al., 2003, Seth et al., 2006, Bergeron et al., 2011). Together with other labs, we have now identified zebrafish mutations in 10 components of the Hh/Gli signaling pathway, including previously uncharacterized or poorly characterized components (e.g. Bergeron et al., 2011, Sekimizu et al., 2004). These mutants provide a powerful set of genetic tools for the study of Hh/Gli signaling during vertebrate development. In 2000 we showed that zebrafish pituitary development requires Hh/Gli signaling (Kondoh et al., 2000), a finding that preceded similar findings in mice (Treier et al., 2001) and humans (Roessler et al., 2003). This work has shed light on human birth defects that affect the forebrain, including holoprosencephaly, which is now linked to mutations in several Hh signaling components.

In the last several years my lab has contributed to a more detailed mechanistic understanding of how Hh/Gli and FGF signaling guide embryonic development of the vertebrate pituitary gland. We showed that Hh/Gli and FGF signaling act as morphogens to guide differentiation of endocrine cells in a concentration-dependent manner (Sbrogna et al., 2003, Guner et al., 2008). We also have elucidated the complex Gli transcription factor code that guides pituitary induction and patterns the placode along the anterior/posterior axis (Devine et al., 2009). More recent work examines the development of the Hypothalamic-Pituitary-Thyroid axis and has led to the surprising finding that excess thyroid hormone is actually toxic to early pituitary thyrotropes, a result that has major implications for human embryonic development that occurs in hyperthyroid mothers (Tonyshkina et al, 2014).  Ksenia also documented the onset of the negative feedback in the thyroid axis, and how this regulation is affected in embyros that grow in hypothyroid environment (Tonyushkina et al, 2017).

We've taken this early Shh work and are now probing the role of Hh signaling in the vertebrate brain throughout the life cycle.  We've now shown that Hh signaling is maintained in the hypothalamic stem cell niche, and that Hh signal levels control neuorgenesis in this region througout life (Male and Ozacar et al, 2020).  We are now interested in understanding how Hh signaling contols growth and morphogenesis in the post-embryonic brain, and whether Hh signaling might play a role in the function of the HPA axis in adults.  The tools and expertise we have developed over the last decade (e.g. Placinta et al, 2009, Shen and Ozacar et al, 2013) make us particularly well positioned to investigate post-embryonic roles for Hh/Gli signaling in the brain at any life stage. It turns out that there is a remarkable evolutionary conservation in the HPA axis, as well as the molecular mechanisms that guide embryogenesis across vertebrate species, including humans. We thus hope our work can help uncover conserved mechanisms of brain growth, stem cell regulation that will some day impact the diagnosis and treatment of human neurodegeneative diseases (stem cel work) or the myriad metabolic and other diseases affecting HPA function in humans.