Hedgehog (HH) signaling is a critical determinant of neural progenitor specification during central nervous system (CNS) development. Subtle changes in Sonic Hedgehog (SHH) ligand concentration are sufficient to specify distinct neural progenitor fates; thus, complex mechanisms exist to precisely control HH ligand production and distribution during CNS development to generate the requisite diversity of mature neurons that comprise a functional CNS. Failures in these regulatory mechanisms underlie numerous CNS disorders. Specifically, deficiencies in HH signaling during embryogenesis prevent proper segregation of the cerebral hemispheres, causing holoprosencephaly, while excess HH signaling impairs neural tube closure, resulting in exencephaly and spina bifida. Additionally, overactive HH signaling is a frequent cause of medulloblastoma, the most common malignant brain tumor in children. The overall goal of this proposal is to reveal novel mechanisms that restrict HH signaling during normal development to uncover fundamental insights into the etiologies of numerous CNS pathologies and to inform the development of novel HH-targeted therapeutics. Restraining the HH response during embryogenesis depends on feedback up-regulation of multiple cell surface HH-binding antagonists, including the canonical HH receptor Patched 1 (PTCH1) and Hedgehog-interacting protein 1 (HHIP1). While loss of feedback up-regulation of PTCH1 or HHIP1 alone has no effect on CNS patterning, combined inactivation of PTCH1- and HHIP1-mediated feedback inhibition results in an increased magnitude and range of HH signaling in the neural tube. Patched 2 (PTCH2) is an additional HH-binding protein that is expressed in the developing CNS during HH-dependent patterning; however, whether PTCH2 restricts HH signaling in vivo remains unknown. My preliminary data suggest that PTCH2 can antagonize HH signaling in cell-based functional assays and can inhibit SHH signaling during CNS patterning via chick in ovo neural tube electroporations. In addition, PTCH2 localizes to the primary cilium, an organelle required for HH signal transduction. Moreover, PTCH2 physically interacts with the HH co-receptor BOC. Based on these data, we hypothesize that PTCH2 is a novel HH antagonist during vertebrate CNS development that functions at the primary cilium to inhibit HH pathway function. I will test this hypothesis through immunofluorescent analysis of neural pattering in Ptch2-/- mouse embryos. To uncover redundancy between PTCH2 and other cell surface antagonists, I will analyze neural patterning in compound Ptch2-/-;Hhip1-/- mice and embryos lacking both PTCH2 and PTCH1 feedback inhibition. I will also employ cell biological approaches to elucidate the mechanism and functional significance of PTCH2 ciliary trafficking. Lastly, I will use biochemical tools to probe the interactions between PTCH2 and other critical cell surface HH components and test the significance of these interactions in cell signaling assays. This analysis will reveal fundamental insights into the nature of HH signal transduction and have therapeutic implications for a multitude of CNS disorders.

Public Health Relevance

Central nervous system (CNS) development is extremely complex and disturbances in this process underlie many neurologic disorders. Hedgehog (HH) signaling plays an essential role during CNS formation and mutations in the HH pathway are associated with a wide range of human diseases; including medulloblastoma; the most common invasive brain tumor in children. My work on novel HH pathway antagonists will reveal critical insights into both normal CNS development and the mechanisms of tumorigenesis in the CNS.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
Project #
Application #
Study Section
NST-2 Subcommittee (NST)
Program Officer
Riddle, Robert D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Anatomy/Cell Biology
Schools of Medicine
Ann Arbor
United States
Zip Code
Mathew, Esha; Collins, Meredith A; Fernandez-Barrena, Maite G et al. (2014) The transcription factor GLI1 modulates the inflammatory response during pancreatic tissue remodeling. J Biol Chem 289:27727-43
Camp, Darius; Haitian He, Billy; Li, Sally et al. (2014) Ihog and Boi elicit Hh signaling via Ptc but do not aid Ptc in sequestering the Hh ligand. Development 141:3879-88