The SDF‐1/CXCR4 pathway and the development of the cerebellar system

Abstract

Mice deficient for the chemokine receptor CXCR4 show premature translocation of granule cell neuroblasts from their germinal zone into the nascent cerebellum [Y.-R. Zuo et al. (1998) Nature, 393, 595-599]. Here, we used CXCR4-null mice to analyse the early development of cerebellar cortical inhibitory interneurons and pontine neurons which, in the adult, are synaptically integrated with granule cells. Cortical inhibitory interneuronal precursors normally invade the cerebellar anlage of CXCR4-deficient mice, but their dispersal is impeded by dislocated foci of proliferating granule cells, from which they are excluded. This is reminiscent of the strict exclusion of inhibitory interneuronal precursors from the superficial external granule cell layer. As inhibitory interneuronal precursors readily mingle with post-mitotic granule cells both in wild-type and CXCR4-null mice, these findings indicate that the developmentally regulated interactions between granule and inhibitory interneuronal precursors are independent of SDF-1 ⁄ CXCR4 signalling. In contrast, the transit of pontine neurons from the rhombic lip through the anterior extramural stream to the basilar pons is disrupted in CXCR4-deficient animals. Migrating pontine neurons express CXCR4, and in CXCR4-null animals these cells are found displaced deep into the brainstem. Consequently, nascent pontine nuclei in CXCR4-deficient animals are hypoplastic. Moreover, they fail to express plexin D1, suggesting that SDF-1 ⁄ CXCR4 signalling may also impinge on axon guidance critical to the orderly formation of granule cell mossy fibre afferents.

Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex

“…Together, these data suggest that Pax2 should be perceived as a marker for early diVerentiating interneuronal precursors. Finally, it is only after they leave the ventricular epithelium that inhibitory interneuronal precursors become positive for Pax2 (Maricich and Herrup 1999); cf also Vilz et al 2005 andZordan et al 2008) which again is in keeping with the observation of Herrup and associates (Maricich and Herrup 1999) that Pax2-positive cells, in contrast to ventricular epithelia, are strictly neuronogenic.…”

Sema3E/PlexinD1 regulates the migration of hem-derived Cajal-Retzius cells in developing cerebral cortex

“…5d), suggesting that the two signalling mechanisms may run parallel. Vilz 34 indicated that Plxnd1 expression is selectively abrogated in pontine nuclei neurons in Cxcr4 o/o mice, in contrast to other cerebellar populations (for example, inferior olive) and forebrain neurons. So, in order to biochemically explore a putative interaction of the two signalling pathways, we used COS1-transfected cells ( Fig.…”

Expression of classical cadherins in the cerebellar anlage: Quantitative and functional aspects

“…The resulting differences in cell adhesivity may be invoked, according to the differential adhesion hypothesis (Steinberg, 1963;Foty and Steinberg, 2005) as one potential determinant of the rather unimpeded passage of the IGL by Pax2-positive inhibitory interneuronal precursors destined for the molecular layer. This interpretation is not contradicted that these latter cells, despite the fact that they express M-, N-and R-cadherin at levels comparable to Math1-EGFP positive granule cell neuroblasts, are strictly excluded from the EGL (Vilz et al, 2005;Weisheit et al, 2006). Rather, this pinpoints the fact that adhesive systems other than the cadherins under scrutiny here are clearly involved in cerebellar histogenesis.…”

“…Therefore, we analyzed the location of inhibitory interneuronal precursors versus that of cells of the granule cell lineage in reaggregate cultures. The availability of GFP-labeled interneuronal precursors allowed us to modify this assay such as to eliminate time consuming and artifact prone tissue processing (Vilz et al, 2005), as whole aggregates could be optically sectioned and analyzed (Fig 6G-P and Q-T). Thus, nascent or manipulated aggregates, which were too frail to withstand embedding and sectioning, became amenable to analysis.…”

“…2B-E, 3) contributes to the delamination of the latter from the external granule cell layer. Unfortunately, this hypothesis cannot be directly tested with our current reaggregation model, as isolated cells rapidly become postmitotic (Baader et al, 1999;Vilz et al, 2005), and small, early aggregates are for reasons of geometry and sensitivity not yet amenable to quantitative analysis of EGFP-expression patterns in a manner comparable to tissue sections. We note, however, that Vilz et al (2005) have reported a patterned distribution, in reaggregates, of granule cells which at the time point of isolation have been in distinct phases of proliferation (and hence may be presumed to also have differed by their cadherin expression based on the present findings).…”