Morphogens play essential developmental roles by conferring fate and positional information to target cells during tissue morphogenesis. The exact processes governing morphogen release from producing cells, and targeting to client cells, are not yet clear. However, evidence is mounting for a novel model of directed delivery for multiple classes of morphogens via specialized filopodia called cytonemes. One such morphogen, Hedgehog (Hh), induces a developmental signaling cascade that, when inappropriately activated, can cause medulloblastoma and basal cell carcinoma. In addition, Hh ligand that is produced by tumor cells has been reported to function in both autocrine and paracrine manners to promote tumor survival. The goals of this proposal are to mechanistically interrogate regulation and function of Dispatched (Disp), an essential regulator of Hh morphogen release, to define the processes governing Hh morphogen export and dispersion. This proposal will test the central hypothesis that Disp shapes the Hh morphogen gradient by directly governing release and dispersion of Hh. This will be achieved through two Specific Aims: 1) Define the mechanism by which Disp facilitates release of lipid-modified Hh. 2) Define the mechanism by which Disp directs Hh dispersion. Upon completion of this work, we will have revealed processes governing Hh dispersion that shape its morphogen gradient during development. This knowledge will enhance our understanding of the mechanisms controlling an essential step in Hh pathway regulation, and may reveal novel methods of targeting the Hh pathway in cancer. Additionally, our findings may reveal shared cellular processes governing transport of other classes of morphogens, as similar regulatory themes are likely in place to allow for proper coordination of essential signaling events during development.
The Hedgehog (Hh) signal transduction pathway plays an essential role in patterning fields of cells during development, and is frequently activated in cancer. Attenuation of Hh signaling during development leads to developmental disorders such as Holoprosencephaly and Pallister-Hall Syndrome. Conversely, inappropriate activation of Hh signaling is causative in basal cell carcinoma, the most common cancer in humans and medulloblastoma, the most common malignant brain tumor in children. In addition, Hh ligand that is produced by tumor cells has been reported to function in both autocrine and paracrine manners to promote tumor survival. As such, the Hh pathway has emerged as an attractive therapeutic target. The goals of this proposal are to dissect the function of Dispatched (Disp), an essential regulator of Hh ligand release, and to define the biological processes governing Hh dispersion to receiving cells. We will achieve these goals through comprehensively analyzing Disp activity using biochemical, cell biological and genetic model systems. Knowledge obtained during the course of the proposed studies will enhance our understanding of the mechanisms controlling an essential step in Hh pathway regulation, and may reveal novel methods of targeting the Hh pathway in disease.
| Stewart, Daniel P; Marada, Suresh; Bodeen, William J et al. (2018) Cleavage activates dispatched for Sonic Hedgehog ligand release. Elife 7: |
| Bodeen, William J; Marada, Suresh; Truong, Ashley et al. (2017) A fixation method to preserve cultured cell cytonemes facilitates mechanistic interrogation of morphogen transport. Development 144:3612-3624 |
