The microcephaly gene Donson is essential for progenitors of cortical glutamatergic and GABAergic neurons
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Sathish Venkataramanappa aff001; Dagmar Schütz aff001; Friederike Saaber aff001; Praveen Ashok Kumar aff001; Philipp Abe aff001; Stefan Schulz aff001; Ralf Stumm aff001
Působiště autorů:
Institute of Pharmacology and Toxicology, Jena University Hospital, Jena, Germany
aff001
Vyšlo v časopise:
The microcephaly gene Donson is essential for progenitors of cortical glutamatergic and GABAergic neurons. PLoS Genet 17(3): e1009441. doi:10.1371/journal.pgen.1009441
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pgen.1009441
Souhrn
Biallelic mutations in DONSON, an essential gene encoding for a replication fork protection factor, were linked to skeletal abnormalities and microcephaly. To better understand DONSON function in corticogenesis, we characterized Donson expression and consequences of conditional Donson deletion in the mouse telencephalon. Donson was widely expressed in the proliferation and differentiation zones of the embryonic dorsal and ventral telencephalon, which was followed by a postnatal expression decrease. Emx1-Cre-mediated Donson deletion in progenitors of cortical glutamatergic neurons caused extensive apoptosis in the early dorsomedial neuroepithelium, thus preventing formation of the neocortex and hippocampus. At the place of the missing lateral neocortex, these mutants exhibited a dorsal extension of an early-generated paleocortex. Targeting cortical neurons at the intermediate progenitor stage using Tbr2-Cre evoked no apparent malformations, whereas Nkx2.1-Cre-mediated Donson deletion in subpallial progenitors ablated 75% of Nkx2.1-derived cortical GABAergic neurons. Thus, the early telencephalic neuroepithelium depends critically on Donson function. Our findings help explain why the neocortex is most severely affected in individuals with DONSON mutations and suggest that DONSON-dependent microcephaly might be associated with so far unrecognized defects in cortical GABAergic neurons. Targeting Donson using an appropriate recombinase is proposed as a feasible strategy to ablate proliferating and nascent cells in experimental research.
Klíčová slova:
Apoptosis – Cerebrum – Hippocampus – Immunostaining – Neocortex – Neurons – Retinal ganglion cells – Piriform cortex
Zdroje
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