The transcriptional repressor RP58 is crucial for cell-division patterning and neuronal survival in the developing cortex

Abstract

The neocortex and the hippocampus comprise several specific layers containing distinct neurons that originate from progenitors at specific development times, under the control of an adequate cell-division patterning mechanism. Although many molecules are known to regulate this cell-division patterning process, its details are not well understood. Here, we show that, in the developing cerebral cortex, the RP58 transcription repressor protein was expressed both in postmitotic glutamatergic projection neurons and in their progenitor cells, but not in GABAergic interneurons. Targeted deletion of the RP58 gene led to dysplasia of the neocortex and of the hippocampus, reduction of the number of mature cortical neurons, and defects of laminar organization, which reflect abnormal neuronal migration within the cortical plate. We demonstrate an impairment of the cell-division patterning during the late embryonic stage and an enhancement of apoptosis of the postmitotic neurons in the RP58-deficient cortex. These results suggest that RP58 controls cell division of progenitor cells and regulates the survival of postmitotic cortical neurons.

RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion

“…By contrast, SATB2 þ layer II-IV neurons were lost or highly reduced in the RP58 cKO (Figure 2a). These results are consistent with previous findings 16 and suggest that RP58 Figure 1 Loss of RP58 produces a novel postnatal microencephalic phenotype with a thin neocortex and absence of corpus callosum. (a-d) Dorsal views at the same magnification of control (a and c) and RP58 cKO (b and d) brains at postnatal (P) day 8 and 15.…”

“…5 and was less than half of that of the control cortex at BP2 (Figures 1g-j and Supplementary Figure 2). Thus, analyses of our cKO mutant extend previous findings with a straight KO, 16 and highlight the requirement of RP58 for normal postnatal brain growth. Critically, loss of RP58 in the CNS leads to a novel postnatal small-brain phenotype with loss of corpus callosum and cerebellar vermis hypoplasia, which resembles the human microencephaly phenotype linked to loss of chromosome-1qter.…”

“…Our CNS-specific conditional strategy and its finding that our cKO and control littermates are indistinguishable at birth allow us to conclude that these defects are CNS-intrinsic and not due to loss of RP58 elsewhere in the body, as may be the case for perinatal death of the total KO reported recently 16 (and this paper). The RP58 cKO mice survive up to 3 weeks at a time when the brain is already well constructed.…”

“…The RP58 cKO mice survive up to 3 weeks at a time when the brain is already well constructed. Starting at P2, cKO brains have a novel postnatal phenotype not observed previously in the straight KOs that die perinatally: 16 reduced neocortex (both in extent and thickness) and loss of corpus callosum.…”

“…16 Critically, perinatal death of conventional knockout (KO) mice 16 precludes analyses in postnatal stages. Furthermore, the reported defects in cell-cycle exit, and in Pax6 þ and Tbr2 þ populations, were deduced from analyses at late corticogenesis stages after embryonic day (E) 16.5, precluding any conclusions on early defects and not providing potential molecular mechanisms for RP58 function during neurogenesis.…”