Aberrant lamination in the cerebral cortex of mouse embryos lacking DNA topoisomerase IIβ

Abstract

We have examined corticogenesis in mouse embryos lacking DNA topoisomerase II␤ (II␤) in the brain or in all tissues. The absence of II␤, a type II DNA topoisomerase normally expressed in postmitotic cells in the developing cortex, severely affects cerebral stratification: no subplate is discernible, and neurons born at later stages of corticogenesis fail to migrate to the superficial layers. This abnormal pattern of neuron positioning in the cerebral cortex is reminiscent of that observed in mouse mutants defective in the reelin-signaling pathway. Significantly, the level of reelin in the neocortex is much reduced when II␤ is absent. These results implicate a role of II␤ in brain development. The enzyme may be required in implementing particular genetic programs in postmitotic cells, such as reelin expression in Cajal-Retzius cells, perhaps through its action on nucleoprotein structure of particular chromosomal regions.M ammalian DNA topoisomerase II␤ (II␤) is a type II DNA topoisomerase that catalyzes the transport of one DNA double-helix through another (1-3). Unlike the II␣ isozyme, which is specifically expressed in proliferating cells and most likely performs the essential function of resolving intertwined chromosome pairs during mitosis (4-6), II␤ is apparently dispensable in cell growth (reviewed in ref. 7). Targeted disruption of the murine TOP2␤ gene showed; however, that II␤ has a critical role in neural and neuromuscular development (8). Whereas top2␤ ϩ/⌬ mice are phenotypically TOP2␤ ϩ and indistinguishable from their TOP2␤ ϩ/ϩ littermates, top2␤ ⌬/⌬ nullizygotes die of a breathing impairment at birth, most likely owing to neural and neuromuscular defects (8).In mammals, II␣ and II␤ are largely expressed in proliferating cells and nonproliferating cells, respectively (7). In a detailed examination of the expression of the two forms during postnatal development of rat cerebellum, a sharp transition from II␣ to II␤ expression was observed in cell populations that had undergone the final division and committed to differentiate into Purkinje or granule cells (9). The amount of DNA-bound II␤ becomes undetectable, however, when cells reach terminal differentiation (10).To further test the role of II␤ in neural development, we have examined cerebral corticogenesis in embryos of mouse lines lacking II␤ in all tissues or specifically in certain brain structures including the telencephalon. We report here that II␤ has a remarkable role in neurogenesis. The induction of II␤ expression, after the final division of cells committed to a neuronal fate, appears necessary for the developmentally regulated expression of certain specific genes in these cells. The role of II␤ is unlikely to be limited to neuronal development and may also be important in the genetic programming of other postmitotic cells. Materials and MethodsConstruction of the Targeting Vector. The left and right arms of TOP2␤-derived sequences, for targeted insertion of DNA sequences between them into the mouse genome, were obtained by PCR. The right ...

Topoisomerase IIβ is required for lamina-specific targeting of retinal ganglion cell axons and dendrites

“…In every case, neurite pathfinding to the retinal or tectal neuropil is preserved, and the wild-type laminar pattern is usually approximated, but fine targeting is disrupted. As in the mouse top2b mutant Lyu and Wang, 2003), the earliest steps of developmentproliferation and mitotic exit -are preserved in zebrafish noto mutants. In the mouse Top2b knockout, laminar organization of neuronal cell bodies in the cortex and pathfinding of some motor and sensory axons are also disrupted, suggesting additional defects in neural patterning not seen here in the zebrafish visual system.…”

Topoisomerase II, not topoisomerase I, is the proficient relaxase of nucleosomal DNA

“…Topo II, rather than topo I, is active in post replicative spermatogenic cells that undergo the nucleo-histone nucleo-protamine transition (Roca and Mezquita, 1989). The b-isoform of topo II found in higher eukaryotes is not required for cell proliferation, but involved in the regulation of cell fate (Lyu and Wang, 2003). The topological interconversions of DNA underlying these molecular processes are largely unknown.…”

Topoisomerase IIβ–Mediated DNA Double-Strand Breaks: Implications in Doxorubicin Cardiotoxicity and Prevention by Dexrazoxane

“…The high efficacy of doxorubicin chemotherapy is thought to be due to the highly elevated expression of Top2a in cancer cells. By contrast, Top2h is present in all cells, including postmitotic cells (18,20,22,23). Recent studies have suggested that Top2h may play a role in transcription (24,25).…”