Advanced Medical Scientist-Programm 2022

Thema: "Role of DONSON in microcephaly and cortical development"

Zusammenfassung:
DONSON is an essential protein that, based on findings in cell lines, exerts multiple functions
in the cell cycle. Recently, biallelic mutations in the DONSON gene were linked to an extraordinary variety of clinically distinct phenotypes of microcephalic dwarfism. Yet, nothing is known about DONSON function in progenitor cells that establish the mammalian organism, and it remains elusive how distinct DONSON mutations cause such a wide spectrum of
clinical phenotypes. We examine DONSON function in mice, focusing on neural progenitors that establish the cerebral cortex. To circumvent early embryonic lethality of Donson-/- mice, we employ conditional Donson knockout mice and a Donson-/P472L model mimicking the DONSON gene defect discovered in two siblings with severe microcephaly in Jena. We will
test if the perturbed DONSON functions in our mouse models affects cell cycle progression, the ATR/ p53-mediated DNA damage response, and centrosome number. We bring to bear immunohistology, flow cytometry, ex utero and in utero electroporation, video microscopy, slice- and neurosphere-cultures, single nuclear RNAseq, and biochemical approaches. We
will significantly advance our understanding of DONSON function in endogenous progenitor cells and how DONSON mutations cause microcephaly and dwarfism.