Abstract
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.
Highlights
Primary microcephaly (PM) is a clinical neurodevelopmental condition defined by a congenital reduction in head circumference of at least 2 standard deviations below the ethnically matched, age- and sex-related mean
Genes encoding proteins that are essential for chromosomal segregation, mitotic division, DNA repair, and DNA damage response are frequently mutated in individuals diagnosed with microcephaly, a clinical condition characterized by cerebrocortical hypotrophy
Recent findings suggest that biallelic mutations in DONSON, a replication fork stabilization factor, cause microcephaly and skeletal defects, but this has not been formally tested
Summary
Primary microcephaly (PM) is a clinical neurodevelopmental condition defined by a congenital reduction in head circumference of at least 2 standard deviations below the ethnically matched, age- and sex-related mean. Since the cerebral cortex constitutes the largest part of the mammalian brain volume and neurogenesis is largely completed before birth, cortical progenitors need to generate neurons with high efficiency, which may render them susceptible to defective cell cycle regulation [3]. Once the cortical network is fully developed, it consists roughly of 80% glutamatergic excitatory neurons (cEN) and 20% GABAergic inhibitory neurons (cIN). The latter population originates in the medial and caudal ganglionic eminence (mGE, cGE) in the subpallium and needs to migrate extensively to reach all cortical areas [12]. Since the correct ratio of cEN versus cIN is essential for proper cortical functioning [13], it is of interest whether a gene implicated in PM is important for progenitors of cEN and progenitors of cIN
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