Principal Investigator:
Nadia Dahmane, PhD and Ariel Ruiz i Altaba, PhD
Developmental Genetics, Skirball Institute and Department of Cell Biology, New York University School of Medicine.

Background
Gli proteins are transcriptional activators that control cell fate, growth, and patterning in many cell types and most organs including the brain, bone, skin, gonads, and lungs. In unstimulated cells, several mechanisms ensure the active repression of Gli target genes. Activation of Gli genes occurs through the Hedgehog (Hh) signal-transduction. When Hh binds to the membrane receptor complex Patched-Smoothened (Ptc-Smo), Smo is released by its repressor, Ptc, and is allowed to signal, thereby leading to Gli protein function.

The Hh-Gli pathway plays an essential role in normal development; however, deregulation of this pathway is responsible for several human diseases, syndromes, and malformations. Constitutively expressed Gli genes have been suggested as the causative agent of basal-cell carcinomas (BCC), rhabdomysosarcomas (RMS), medulloblastomas (MB), and brain tumors. The loss or misfunction of Gli proteins appear to cause Greig's cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS) and lead to malformations seen in patients with post-axial polydactyly type A (PAP-A) defects. Therapeutic agents that ensure the proper regulation and expression of Gli proteins could prevent or treat many of these diseases.

Description of project
In vertebrates, three Gli genes with dual function have been described in several species. The N-terminal region encodes a repressor function whereas C-terminal regions are required for inducing activity. Repressors are constitutively nuclear, and act as dominant-negative forms while activating constructs appear to be mostly cytoplasmic and briefly translocate to the nucleus.

The present invention identifies C-terminal Gli protein truncates as dominant-negative repressors. Our findings indicate that all primary human brain, skin and prostate tumors tested express the Gli genes and that Gli proteins can induce tumor development in the brain of an experimental animal. Further, the addition of Gli truncate forms prevents tumor growth by inhibition of Gli function. Therefore, Gli truncate forms may serve as an effective therapeutic for prevention or treatment of brain tumors. That expression of full-length Gli proteins enhances proliferation of normal precursor cells in the brain suggest that these proteins may also be used to increase proliferation of precursors in neuro-degenerative diseases.

Dr. Ruiz i Altaba, an expert in the field of developmental cell biology and developmental neurobiology, has recently published several papers related to these findings. For more in-depth explanations of the invention and potential applications, please refer to "Gli proteins and Hedgehog signaling: development and cancer" (Trends in Genetics 15:418-425) or "The works of Gli and the power of Hedgehog" (Nature Cell Biology 1:147-148).

Application
The identification of C-terminal Gli truncates as a repressor of neuronal differentiation indicates that targeting of Gli proteins may be an effective mechanism to prevent or treat brain tumor formation as well as to other tumors in different organs. The identification of constitutively expressed Gli proteins in skin cancers such as basal-cell carcinomas (BCC) and muscles cancers such as rhabdomysosarcomas (RMS) suggest that identified therapeutics may be effective in treating a wide range of cancers. The full length Gli proteins may also be used to increase proliferation of precursors in neuro-degenerative diseases such as such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), Parkinson's disease, and memory loss. Lastly, that several human syndromes and malformations such as Greig's cephalopolysyndactyly syndrome (GCPS), Pallister-Hall syndrome (PHS) and post-axial polydactyly type A (PAP-A) defects are associated with the absence or misfunction of Gli proteins makes these proteins a prime target for therapeutics directed towards these disorders.

Patent Status
A patent application has been filed.