Neogenin1 is a sonic hedgehog target in medulloblastoma and is necessary for cell cycle progression

Abstract

The canonical Sonic Hedgehog (Shh)/Gli pathway plays multiples roles during central nervous system (CNS) development. To elucidate the molecular repertoire of Shh mediators, we have recently described novel transcriptional targets in response to Shh pathway modulation. Among them, we were able to identify Neogenin1 (Neo1), a death dependence receptor, as a new direct Shh downstream regulator in neural precursor proliferation. As appropriate Shh signaling is required for cerebellar growth and alterations cause Shh-driven medulloblastoma (MB), here we have addressed the role of the Shh/Neogenin1 interaction in the context of cerebellar development and cancer. We demonstrate that the Shh pathway regulates Neogenin1 expression in mouse models that recapitulate the Shh MB subtype. We show that the canonical Shh pathway directly regulates the Neo1 gene acting through an upstream sequence in its promoter both in vitro and in vivo in granule neuron precursor cells. We also identified and characterized a functional Gli-binding site in the first intron of the human NEO1 gene. Gene expression profiling of more than 300 MB shows that NEO1 is indeed upregulated in SHH tumors compared to the other MB subgroups. Finally, we provide evidence that NEO1 is necessary for cell cycle progression in a human MB cell line, because a loss of function of NEO1 arrests cells in the G2/M phase. Taken together, these results highlight Neogenin1 as a novel downstream effector of the Shh pathway in MB and a possible therapeutic target.Medulloblastoma (MB), a primitive neuroepithelial tumor, is the most common malignant childhood primary central nervous system (CNS) tumor. Current treatment protocols encompassing surgical resection, chemotherapy and radiotherapy contributed to a better prognosis of MB patients. However, approximately one-third of the MB patients remain incurable and recurrence remains frequent.

Neogenin, Defined as a GD3-associated Molecule by Enzyme-mediated Activation of Radical Sources, Confers Malignant Properties via Intracytoplasmic Domain in Melanoma Cells

“…However, implication of neogenin in cancer phenotypes is now controversial, i.e. neogenin was considered as a suppressor gene as deleted in colorectal cancer (DCC) in breast cancers (42) and gliomas (43), and it was also reported as a cancer-promoting gene in gastric cancers (45), medulloblastomas (40), and esophageal cancers (46).…”

Medulloblastoma Down Under 2013: a report from the third annual meeting of the International Medulloblastoma Working Group

“…In particular, he discussed Neogenin1 ( NEO1 ) [22], an axon-guidance molecule involved in chemoattraction during axon growth. Low levels of NEO1 expression adversely affects prognosis in patients with SHH disease, but it is unclear how the molecule functions in this context.…”

Netrin-1 Promotes Medulloblastoma Cell Invasiveness and Angiogenesis, and Demonstrates Elevated Expression in Tumor Tissue and Urine of Patients with Pediatric Medulloblastoma

“…While the Shh group has an overall survival rate that falls in the middle of the four subgroups, a distinct subset of invasive, anaplastic Shh tumors has the worst prognosis of any group, underscoring the impact of invasion on survival. Shh activity is relevant to netrin-1 since neogenin, a netrin receptor, is a Shh target in MB and is required for MB cell cycle progression (4). The expression of another axonal guidance receptor, neuropilin 1 (NRP1), correlates with poor overall survival in MB patients, but receptor blockade inhibits the growth and metastasis of MB (5).…”