This Atoh1-CS-primary cilium-SHH pro-proliferative pathway is also conserved in SHH-type medulloblastoma, a pediatric brain tumor arising from the GNPs.
Our work reveals a dynamic ATOH1-driven molecular cascade underlying medulloblastoma metastasis that offers possible therapeutic opportunities.<i></i>.
Hence, the crosstalk between SHH signaling and Atoh1 during cerebellar development highlights a collaborative network that could be further targeted in medulloblastoma.
We found that the transcription factor NEUROG1 (but not ATOH1) is expressed in cLPN, unlike normal adult cerebellum, and that fatty acid binding protein 4 (FABP4), typically found in adipocytes, is significantly overexpressed compared with both normal adult cerebellum and human MB.
Therefore, by targeting multiple genes regulating the differentiation state of GNPs, Atoh1 collaborates with the pro-proliferative Gli1-dependent transcriptional program to influence medulloblastoma development.
Recently, we showed that HIC1 is a direct transcriptional repressor of ATOH1, a proneural transcription factor required for normal cerebellar development, as well as for medulloblastoma cell viability.
Given that Atoh1 is also a putative target of Hh signaling, we conclude that the Hic1 and Ptch1 tumor suppressors cooperate to silence Atoh1 expression during a critical phase in GCP differentiation in which malignant transformation may lead to medulloblastoma.
Given that Atoh1 is also a putative target of Hh signaling, we conclude that the Hic1 and Ptch1 tumor suppressors cooperate to silence Atoh1 expression during a critical phase in GCP differentiation in which malignant transformation may lead to medulloblastoma.
GLI1 transcript was expressed in medulloblastomas with ATOH1 transcript, whereas high levels of MYC transcript were unrelated to NEUROG1 or ATOH1 expression.