Our goal is to understand the mechanisms by which information encoded in an extracellular signal is converted into complex patterns in the developing mammalian embryo. This proposal focuses on the role of Sonic hedgehog (Shh) signaling. The Shh signaling pathway is not only essential for the induction of clinically relevant neurons within the CNS, but inappropriate activation of Shh signaling has been linked to the development of several types of tumor, most notably basal cell carcinoma (BCC) (the most common form of skin cancer), medulloblastoma (the most common brain tumor of children) and rhabdomyosarcoma (the most prevalent soft tissue cancer in children). Further, loss of Hedgehog (HH) signaling underlies several birth defects that include holoprosencephaly. Consequently, understanding how a Shh signal is received, transduced and modulated is likely to lead to new biological insights with direct relevance to human health. Given the close human parallel and advantages of available genetic approaches, the mouse is our principle experimental system.
Aim 1 proposes to explore the biological significance of cholesterol modification of Shh investigating the role of a Dispatched gene in Shh release and the requirement for cholesterol in Shh-mediated patterning of the neural tube. A GFP tagged Shh protein will be generated to study Shh movement in vivo.
Aim 2 proposes to explore the genetic interactions amongst several Shh-binding proteins (Ptch1, Ptch2, Gas1 and Hip1) that appear to act in Shh-mediated feedback control as they relate to neural patterning. We will map the interaction domains between Shh and one of these, Hip1.
Aim 3 will explore the roles of several novel targets of HH-signaling identified in transcriptional screens.
Aim 4 proposes to characterize a new inducible model of HH-mediated tumorigenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS033642-16
Application #
7751918
Study Section
Special Emphasis Panel (ZRG1-DEV-1 (01))
Program Officer
Mamounas, Laura
Project Start
1994-12-01
Project End
2011-11-30
Budget Start
2009-12-01
Budget End
2010-11-30
Support Year
16
Fiscal Year
2010
Total Cost
$851,845
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Hettmer, Simone; Lin, Michael M; Tchessalova, Daria et al. (2016) Hedgehog-driven myogenic tumors recapitulate skeletal muscle cellular heterogeneity. Exp Cell Res 340:43-52
Nishi, Yuichi; Zhang, Xiaoxiao; Jeong, Jieun et al. (2015) A direct fate exclusion mechanism by Sonic hedgehog-regulated transcriptional repressors. Development 142:3286-93
Lopez-Rios, Javier; Duchesne, Amandine; Speziale, Dario et al. (2014) Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs. Nature 511:46-51
Rajurkar, M; Huang, H; Cotton, J L et al. (2014) Distinct cellular origin and genetic requirement of Hedgehog-Gli in postnatal rhabdomyosarcoma genesis. Oncogene 33:5370-8
Junker, Jan Philipp; Peterson, Kevin A; Nishi, Yuichi et al. (2014) A predictive model of bifunctional transcription factor signaling during embryonic tissue patterning. Dev Cell 31:448-60
Junker, Jan Philipp; Noël, Emily S; Guryev, Victor et al. (2014) Genome-wide RNA Tomography in the zebrafish embryo. Cell 159:662-75
Holtz, Alexander M; Peterson, Kevin A; Nishi, Yuichi et al. (2013) Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning. Development 140:3423-34
Hettmer, Simone; Teot, Lisa A; van Hummelen, Paul et al. (2013) Mutations in Hedgehog pathway genes in fetal rhabdomyomas. J Pathol 231:44-52
Peterson, Kevin A; Nishi, Yuichi; Ma, Wenxiu et al. (2012) Neural-specific Sox2 input and differential Gli-binding affinity provide context and positional information in Shh-directed neural patterning. Genes Dev 26:2802-16
Rajurkar, Mihir; De Jesus-Monge, Wilfredo E; Driscoll, David R et al. (2012) The activity of Gli transcription factors is essential for Kras-induced pancreatic tumorigenesis. Proc Natl Acad Sci U S A 109:E1038-47

Showing the most recent 10 out of 81 publications