Abstract
Differentiated neurons and glia are acquired from immature precursors via transcriptional controls exerted by factors such as proteins in the family of Glial Cells Missing (Gcm). Mammalian Gcm proteins mediate neural stem cell induction, placenta and parathyroid development, whereas Drosophila Gcm proteins act as a key switch to determine neuronal and glial cell fates and regulate hemocyte development. The present study reports a hypoparathyroidism-associated mutation R59L that alters Drosophila Gcm (Gcm) protein stability, rendering it unstable, and hyperubiquitinated via the ubiquitin-proteasome system (UPS). GcmR59L interacts with the Slimb-based SCF complex and Protein Kinase C (PKC), which possibly plays a role in its phosphorylation, hence altering ubiquitination. Additionally, R59L causes reduced Gcm protein levels in a manner independent of the PEST domain signaling protein turnover. GcmR59L proteins bind DNA, functionally activate transcription, and induce glial cells, yet at a less efficient level. Finally, overexpression of either wild-type human Gcmb (hGcmb) or hGcmb carrying the conserved hypoparathyroidism mutation only slightly affects gliogenesis, indicating differential regulatory mechanisms in human and flies. Taken together, these findings demonstrate the significance of this disease-associated mutation in controlling Gcm protein stability via UPS, hence advance our understanding on how glial formation is regulated.
Highlights
A fundamental issue during development is how individual cells acquire their identities from undefined precursors and mature into distinct cell types with functional features
Our previous investigation has shown that Glial Cells Missing (Gcm) undergoes ubiquitination-mediated protein degradation and its protein stability is crucial for glial cell development in Drosophila embryos[28]
We sought to determine if the attenuated Repo-positive cells conferred by Gcm proteins carrying a hypoparathyroidism-related mutation R59L (GcmR59L) is due to a differential rate in continuous induction of glial cells due to compromised protein stability
Summary
A fundamental issue during development is how individual cells acquire their identities from undefined precursors and mature into distinct cell types with functional features. Does Gcm play a role in neural precursor cell specification, it promotes glial differentiation by activating downstream target genes such as reversed polarity (repo) and pointed (pnt)[11,12], and represses the neuronal fate through the activation of tramtrack (ttk). New studies have shown that genes in the mammalian gcm family are essential for neural stem cell induction, further strengthening the role of these proteins in the developing nervous system[22,23] Together, these findings have underscored the importance of Gcm proteins and make them reasonable targets for precise regulation on their activity. Glial cell number is not largely affected when human Gcmb (hGcmb) carrying the same mutation is overexpressed These results suggest that the disease-related R59L mutation causes distorted Gcm protein stability via SCF complex-dependent ubiquitination and degradation, playing an important role in glial cell development
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