Abstract
BackgroundDuring the development of the mammalian cerebral cortex, newborn postmitotic projection neurons are born from local neural stem cells and must undergo radial migration so as to position themselves appropriately to form functional neural circuits. The zinc finger transcriptional repressor Rp58 (also known as Znf238 or Zbtb18) is critical for coordinating corticogenesis, but its underlying molecular mechanism remains to be better characterised.FindingsHere, we demonstrate that the co-expression of Rp58 and the cyclin dependent kinase inhibitor (CDKI) p27kip1 is important for E14.5-born cortical neurons to coordinate cell cycle exit and initiate their radial migration. Notably, we find that the impaired radial positioning of Rp58-deficient cortical neurons within the embryonic (E17.5) mouse cortex, as well as their multipolar to bipolar transition from the intermediate zone to the cortical plate can be restored by forced expression of p27kip1 in concert with suppression of Rnd2, a downstream target gene of Rp58. Furthermore, the restorative effects of p27kip1 and Rnd2 abrogation are reminiscent of suppressing RhoA signalling in Rp58-deficient cells.ConclusionsOur findings demonstrate functional interplay between a transcriptional regulator and a CDKI to mediate neuroprogenitor cell cycle exit, as well as to promote radial migration through a molecular mechanism consistent with suppression of RhoA signalling.
Highlights
The development of the cerebral cortex involves a precise integration of multiple molecular cues within embryonic cortical cells to coordinate the production of appropriate numbers of progenitor cells, followed by the elaboration of distinct neural cell types [1,2,3,4]
We focussed our attention on early-mid gestation mouse embryos at embryonic day 14.5 (E14.5), a stage of neurodevelopment defined by a peak period of neurogenesis when maximal numbers of cortical neurons are born from local ventricular zone (VZ) and subventricular zone (SVZ) progenitor cells [23]
Since it is known that disruptions to Repressor Protein of 58 kDa (Rp58) or p27kip1 lead to defective neuronal differentiation and radial migration [10, 11, 13, 16], we reasoned that the combined activities of both Rp58 and p27kip1 might be relevant for coordinating the cellular activities of cortical progenitors, such as their cell cycle exit and radial migration
Summary
The development of the cerebral cortex involves a precise integration of multiple molecular cues within embryonic cortical cells to coordinate the production of appropriate numbers of progenitor cells, followed by the elaboration of distinct neural cell types [1,2,3,4]. The activities of DNA-binding transcription factors have been recognised to be crucial for guiding the developmental trajectory of embryonic cortical neurons through the initiation of cell-intrinsic programmes which specify their subtype as excitatory, glutamatergic neurons or inhibitory, GABAergic neurons [3, 5,6,7]. The activities of transcriptional repressors, such as the zinc finger DNA binding transcriptional repressor Rp58 ( known as Znf238 or Zbtb18), are critical to the development of the embryonic. During the development of the mammalian cerebral cortex, newborn postmitotic projection neurons are born from local neural stem cells and must undergo radial migration so as to position themselves appropriately to form functional neural circuits. The zinc finger transcriptional repressor Rp58 ( known as Znf238 or Zbtb18) is critical for coordinating corticogenesis, but its underlying molecular mechanism remains to be better characterised
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