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Identifying the biologically active forms of HEDGEHOG proteins.

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Author	Tokhunts, Robert
Title	Identifying the biologically active forms of HEDGEHOG proteins.
Date	2012
Abstract	Hedgehog (HH) proteins play an important and evolutionary conserved patterning role in metazoan development. Aside from this physiological role, pathologically HH proteins are implicated in human developmental disorders and post-developmental reactivation of these proteins is required for continued viability of an expanding array of cancers. Biogenesis of HH proteins begins with the production of 45 kDa HH Full Length (HH-FL) preproteins that according to the most widely accepted model are retained intracellularly and are incapable of signaling. To become signaling species HH-FL proteins require full processing to a 19 kDa fragment that undergoes dual lipid modifications by two different lipids - a palmitate and cholesterol. This dual lipid-modified 19 kDa fragment (HH-Np) is then able to traffic to the cell membrane and become secreted. Once in the extracellular matrix, fully processed HH proteins elicit biological effects by establishing a concentration gradient that extends for many cell diameters. To initiate our studies we asked as to how hydrophobic, dual lipid-modified fully processed HH-Np proteins are able to traverse hydrophilic extracellular matrix. Additionally as the HH lipid modifications have been identified under unnaturally high over-expressed cell culture conditions, we asked whether the biologically relevant identities of lipid modifications could be different. We began investigating these questions by studying, as a function analysis tool, pathological single point mutants of HH proteins that were identified in patients with the developmental disorder Holoprosencephaly. Aside from describing the biological significance of some of these point mutations we readily realized that HH-FL proteins are biologically active - constituting novel HH protein signaling species. Additionally, we also identified a wide array of lipid modifications of HH-Np proteins, gaining unexpected insights into HH functions. Together, these data show that HH biogenesis is more complicated than previously thought and provide a model that better reconciles both our and published observations from other laboratories. In our studies we used a combination of molecular and cell biology techniques, biochemistry, and microscopy methods to elucidate these aspects of HH signaling. Additionally, in our studies, we employed relevant animal models including chicken embryo, mouse and Drosophila systems.
Description	1 online resource (xvi, 211 leaves) : illustrations (some color)
Format	application/pdf
Advisor	Dmitrovsky, Ethan ; Robbins, David ; Hwa, John ; Chang, T.Y.
College	Dartmouth Medical School -- Department of Experimental and Molecular Medicine.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D)--Dartmouth College.
Copyright	In Copyright. This material is protected by copyright and/or related rights. You are free to use this material in any way that is permitted by copyright law that applies to your use. For other uses, you need to obtain permission from the rights-holder(s). http://rightsstatements.org/page/InC/1.0/
DOI	https://doi.org10.1349/ddlp.2902

Title	tokhunts2012 1
Full Text	Identifying the biologically active forms of HEDGEHOG proteins A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Experimental and Molecular Medicine by Robert Tokhunts DARTMOUTH COLLEGE Hanover, New Hampshire March 20, 2012.

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