Modulation of cell-cycle dynamics is required to regulate the number of cerebellar GABAergic interneurons and their rhythm of maturation

Abstract

SUMMARYThe progenitors of cerebellar GABAergic interneurons proliferate up to postnatal development in the prospective white matter, where they give rise to different neuronal subtypes, in defined quantities and according to precise spatiotemporal sequences. To investigate the mechanisms that regulate the specification of distinct interneuron phenotypes, we examined mice lacking the G1 phase-active cyclin D2. It has been reported that these mice show severe reduction of stellate cells, the last generated interneuron subtype. We found that loss of cyclin D2 actually impairs the whole process of interneuron genesis. In the mutant cerebella, progenitors of the prospective white matter show reduced proliferation rates and enhanced tendency to leave the cycle, whereas young postmitotic interneurons undergo severe delay of their maturation and migration. As a consequence, the progenitor pool is precociously exhausted and the number of interneurons is significantly reduced, although molecular layer interneurons are more affected than those of granular layer or deep nuclei. The characteristic inside-out sequence of interneuron placement in the cortical layers is also reversed, so that later born cells occupy deeper positions than earlier generated ones. Transplantation experiments show that the abnormalities of cyclin D2 -/-interneurons are largely caused by cell-autonomous mechanisms. Therefore, cyclin D2 is not required for the specification of particular interneuron subtypes. Loss of this protein, however, disrupts regulatory mechanisms of cell cycle dynamics that are required to determine the numbers of interneurons of different types and impairs their rhythm of maturation and integration in the cerebellar circuitry.

Circuit- and Diagnosis-Specific DNA Methylation Changes at γ-Aminobutyric Acid–Related Genes in Postmortem Human Hippocampus in Schizophrenia and Bipolar Disorder

“…48 Mice deficient in CCND2 have been developed as a model of hippocampal hyperactivity displaying multiple cognitive deficits and molecular abnormalities observed in SZ. 49 The third most significant DMR and the greatest number of DMRs were found at DAXX , which codes for death-associated protein 6, a heterochromatin-associated transcriptional regulator active in cell cycle control.…”

The Genesis of Cerebellar GABAergic Neurons: Fate Potential and Specification Mechanisms

“…Other environmental factors, such as basic fibroblast growth factor (Lee et al, 2005), Shh (Huang et al, 2010), or thyroid hormones (Manzano et al, 2007), also contribute to regulate the production rates of interneurons. Similarly, cell-intrinsic mechanisms that control cell cycle progression and length also appear to be relevant for the proper outcome of these processes (Lee et al, 2009; Leto et al, 2011). …”

“…For instance, inactivation of Xrcc1, a DNA repair protein, produces a dramatic loss of GABAergic interneurons due to p53-dependent cell cycle arrest occurring at the moment when progenitor cells start to differentiate (Lee et al, 2009). Likewise, mice lacking the G1-phase active protein cyclin D2 show a severe loss of stellate cells (Huard et al, 1999) and a severe delay in interneuron maturation (Leto et al, 2011). At least for the latter mice, however, the progenitors’ capacity to acquire distinct mature phenotypes is not affected (Leto et al, 2011).…”

Selective transgene expression in cerebellar Purkinje cells and granule cells using adeno-associated viruses together with specific promoters

“…AAVs were injected at around 10-days old, when the development of their cerebellar cortex is still ongoing, and the infection of AAV would be affected by the developmental stage of each type of neuron. Although the precise time course of the development of inhibitory interneurons is not completely understood, stellate/basket cells are generated postnatally through proliferation, migration, and maturation (Leto et al, 2011;Zhang and Goldman, 1996). Furthermore, cerebellar cortical interneurons differentiate in an inside-out manner (Leto et al, 2009;Sudarov et al, 2011).…”