Heterogeneity and Bipotency of Astroglial-Like Cerebellar Progenitors along the Interneuron and Glial Lineages

Abstract

Cerebellar GABAergic interneurons in mouse comprise multiple subsets of morphologically and neurochemically distinct phenotypes located at strategic nodes of cerebellar local circuits. These cells are produced by common progenitors deriving from the ventricular epithelium during embryogenesis and from the prospective white matter (PWM) during postnatal development. However, it is not clear whether these progenitors are also shared by other cerebellar lineages and whether germinative sites different from the PWM originate inhibitory interneurons. Indeed, the postnatal cerebellum hosts another germinal site along the Purkinje cell layer (PCL), in which Bergmann glia are generated up to first the postnatal weeks, which was proposed to be neurogenic. Both PCL and PWM comprise precursors displaying traits of juvenile astroglia and neural stem cell markers. First, we examine the proliferative and fate potential of these niches, showing that different proliferative dynamics regulate progenitor amplification at these sites. In addition, PCL and PWM differ in the generated progeny. GABAergic interneurons are produced exclusively by PWM astroglial-like progenitors, whereas PCL precursors produce only astrocytes. Finally, through in vitro, ex vivo, and in vivo clonal analyses we provide evidence that the postnatal PWM hosts a bipotent progenitor that gives rise to both interneurons and white matter astrocytes.

Distinct roles of neuroepithelial-like and radial glia-like progenitor cells in cerebellar regeneration

“…By contrast, the activity of ptf1a-expressing VZ progenitor cells is largely exhausted in the adult cerebellum, and the loss correlates with the very rare genesis of interneurons, Bergmann glia and oligodendrocytes. The postembryonic VZ progenitor cells in the zebrafish cerebellum share many similarities with the recently identified bi-potent astroglial progenitors in the mouse cerebellar white matter (Parmigiani et al, 2015). Furthermore, other VZ progenitor cell-derived cell types, such as Purkinje and eurydendroid cells, are not produced beyond juvenile stages.…”

Sonic hedgehog patterning during cerebellar development

“…Cells in the deepest part of EGL, as well as in the ML and in the internal granular layer (IGL), do not express cyclin-D1, indicating their status of non-proliferating cells [119][120][121]. Thus, at the time when they are ready to leave the proliferative niche, GCPs undergo some cell-autonomous changes that are critical to exit the cell cycle.…”

Apical complex protein Pals1 is required to maintain cerebellar progenitor cells in a proliferative state

“…S4). This suggests either that the number of VZ-derived bipotent white matter progenitor cells, which generate both glia and interneurons (Parmigiani et al, 2015), is reduced or that their proliferation is defective.…”

“…The Pals1-deficient white matter, another non-epithelial germinal zone in the cerebellum, also showed significantly reduced progenitor populations labeled by Sox9 or Ki67. Although distinct mitogenic signals and/or cyclins are utilized in different germinal zones (Chen et al, 2013;Julian et al, 2010;Parmigiani et al, 2015), the common function of Pals1 in each germinal zone indicates that it might play a central role in cell cycle progression for all cerebellar progenitors. Despite the reduction of the total progenitor pool in the Pals1 mutant, the S-phase fraction of cycling cells was unchanged, suggesting that Pals1 loss forces progenitors to exit the cell cycle without obviously altering total cell cycle or S-phase lengths.…”