hGFAP-mediated GLI2 overexpression leads to early death and severe cerebellar malformations with rare tumor formation

Judith Niesen; Irm Hermans-Borgmeyer; Christina Krüger; Melanie Schoof; Franziska Modemann; Ulrich Schüller

doi:10.1016/j.isci.2023.107501

hGFAP-mediated GLI2 overexpression leads to early death and severe cerebellar malformations with rare tumor formation

iScience. 2023 Jul 28;26(9):107501. doi: 10.1016/j.isci.2023.107501. eCollection 2023 Sep 15.

Authors

Judith Niesen^{1

2

3}, Irm Hermans-Borgmeyer⁴, Christina Krüger^{2

3}, Melanie Schoof^{2

3}, Franziska Modemann^{1

5}, Ulrich Schüller^{2

3

6}

Affiliations

¹ Mildred Scheel Cancer Career Centre HaTriCS4, University Medical Centre Hamburg-Eppendorf, 20251 Hamburg, Germany.
² Research Institute Children's Cancer Centre, 20251 Hamburg, Germany.
³ Department of Pediatric Hematology and Oncology, University Medical Centre Hamburg-Eppendorf, 20251 Hamburg, Germany.
⁴ Scientific Service Group for Transgenic Animals, University Medical Centre Hamburg-Eppendorf, 20251 Hamburg, Germany.
⁵ Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, II. Department of Internal Medicine, University Medical Centre Hamburg-Eppendorf, 20251 Hamburg, Germany.
⁶ Institute of Neuropathology, University Medical Centre Hamburg-Eppendorf, 20251 Hamburg, Germany.

Abstract

The zinc-finger transcription factor GLI2 is frequently amplified in childhood medulloblastoma of the Sonic-hedgehog type (SHH-MB), with or without amplification of NMYC or deletion of TP53. Despite the aggressive tumor behavior, tumorigenesis is not well understood, and adequate mouse models are lacking. Therefore, we generated mice with a GLI2 overexpression under control of the hGFAP-promoter. These mice died within 150 days. The majority only survived until postnatal day 40. They displayed severe cerebellar hypoplasia, cortical malformations, but no brain tumors, except for one out of 23 animals with an undifferentiated hindbrain lesion. Additional loss of p53 did not result in cerebellar tumors, but partially rescued the cerebellar phenotype induced by GLI2 overexpression. Similarly, the combination of GLI2 and NMYC was neither sufficient for the development of SHH-MB. We therefore assume that the development of childhood SHH-MB in mice is either occurring in cellular origins outside the hGFAP-positive lineage or needs additional genetic drivers.

Keywords: Biological sciences; Cancer; Molecular biology.