ABSTRACT
Astrocytes are crucial in the formation, fine-tuning, function and plasticity of neural circuits in the central nervous system. However, important questions remain about the mechanisms instructing astrocyte cell fate. We have studied astrogenesis in the ventral nerve cord of Drosophila larvae, where astrocytes exhibit remarkable morphological and molecular similarities to those in mammals. We reveal the births of larval astrocytes from a multipotent glial lineage, their allocation to reproducible positions, and their deployment of ramified arbors to cover specific neuropil territories to form a stereotyped astroglial map. Finally, we unraveled a molecular pathway for astrocyte differentiation in which the Ets protein Pointed and the Notch signaling pathway are required for astrogenesis; however, only Notch is sufficient to direct non-astrocytic progenitors toward astrocytic fate. We found that Prospero is a key effector of Notch in this process. Our data identify an instructive astrogenic program that acts as a binary switch to distinguish astrocytes from other glial cells.
Subject(s)
Astrocytes/cytology , DNA-Binding Proteins/genetics , Drosophila Proteins/genetics , Drosophila melanogaster/embryology , Nerve Tissue Proteins/genetics , Neuropil/cytology , Nuclear Proteins/genetics , Proto-Oncogene Proteins/genetics , Receptors, Notch/genetics , Transcription Factors/genetics , Animals , Astrocytes/metabolism , Cell Lineage/physiology , Central Nervous System/embryology , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/metabolism , Drosophila Proteins/biosynthesis , Drosophila Proteins/metabolism , Excitatory Amino Acid Transporter 1/antagonists & inhibitors , Excitatory Amino Acid Transporter 1/biosynthesis , Excitatory Amino Acid Transporter 2/biosynthesis , Excitatory Amino Acid Transporter 2/genetics , Gene Expression Regulation, Developmental , Nerve Tissue Proteins/metabolism , Neurogenesis/physiology , Neuroglia/cytology , Proto-Oncogene Proteins/metabolism , RNA Interference , RNA, Small Interfering/genetics , Receptors, Notch/metabolism , Transcription Factors/metabolismABSTRACT
Spinocerebellar ataxia type 3 is caused by the expansion of the coding CAG repeat in the ATXN3 gene. Interestingly, a -1 bp frameshift occurring within an (exp)CAG repeat would henceforth lead to translation from a GCA frame, generating polyalanine stretches instead of polyglutamine. Our results show that transgenic expression of (exp)CAG ATXN3 led to -1 frameshifting events, which have deleterious effects in Drosophila and mammalian neurons. Conversely, transgenic expression of polyglutamine-encoding (exp)CAA ATXN3 was not toxic. Furthermore, (exp)CAG ATXN3 mRNA does not contribute per se to the toxicity observed in our models. Our observations indicate that expanded polyglutamine tracts in Drosophila and mouse neurons are insufficient for the development of a phenotype. Hence, we propose that -1 ribosomal frameshifting contributes to the toxicity associated with (exp)CAG repeats.
