Metazoan development depends on tightly regulated gene expression programs that instruct progenitor cells to adopt specialized fates. Recent work found that posttranslational modifications, such as ...monoubiquitylation, can determine cell fate also independently of effects on transcription, yet how monoubiquitylation is implemented during development is poorly understood. Here, we have identified a regulatory circuit that controls monoubiquitylation-dependent neural crest specification by the E3 ligase CUL3 and its substrate adaptor KBTBD8. We found that CUL3
monoubiquitylates its essential targets only after these have been phosphorylated in multiple motifs by CK2, a kinase whose levels gradually increase during embryogenesis. Its dependency on multisite phosphorylation allows CUL3
to convert the slow rise in embryonic CK2 into decisive recognition of ubiquitylation substrates, which in turn is essential for neural crest specification. We conclude that multisite dependency of an E3 ligase provides a powerful mechanism for switch-like cell fate transitions controlled by monoubiquitylation.
Metazoan development depends on the accurate execution of differentiation programs that allow pluripotent stem cells to adopt specific fates. Differentiation requires changes to chromatin ...architecture and transcriptional networks, yet whether other regulatory events support cell-fate determination is less well understood. Here we identify the ubiquitin ligase CUL3 in complex with its vertebrate-specific substrate adaptor KBTBD8 (CUL3(KBTBD8)) as an essential regulator of human and Xenopus tropicalis neural crest specification. CUL3(KBTBD8) monoubiquitylates NOLC1 and its paralogue TCOF1, the mutation of which underlies the neurocristopathy Treacher Collins syndrome. Ubiquitylation drives formation of a TCOF1-NOLC1 platform that connects RNA polymerase I with ribosome modification enzymes and remodels the translational program of differentiating cells in favour of neural crest specification. We conclude that ubiquitin-dependent regulation of translation is an important feature of cell-fate determination.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Gene Ontology analyses of autism spectrum disorders (ASD) risk genes have repeatedly highlighted synaptic function and transcriptional regulation as key points of convergence. However, these analyses ...rely on incomplete knowledge of gene function across brain development. Here we leverage Xenopus tropicalis to study in vivo ten genes with the strongest statistical evidence for association with ASD. All genes are expressed in developing telencephalon at time points mapping to human mid-prenatal development, and mutations lead to an increase in the ratio of neural progenitor cells to maturing neurons, supporting previous in silico systems biological findings implicating cortical neurons in ASD vulnerability, but expanding the range of convergent functions to include neurogenesis. Systematic chemical screening identifies that estrogen, via Sonic hedgehog signaling, rescues this convergent phenotype in Xenopus and human models of brain development, suggesting a resilience factor that may mitigate a range of ASD genetic risks.
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•In vivo analysis of autism genes reveals a convergent vulnerability in neurogenesis•Systems biological analysis implicates the inner cortical plate and subventricular zone•Estrogen can mitigate the effects of disparate autism gene mutations•Estrogen inhibits Sonic hedgehog signaling
Using parallel in vivo analyses and systems biological approaches, Willsey et al. implicate cortical neurogenesis as a point of convergent vulnerability in autism spectrum disorders. They identify estrogen as a resilience factor for multiple, disparate autism genes and reveal a conserved role for estrogen in repressing Sonic hedgehog signaling.
Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a ...large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward—an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.
A collaborative interdisciplinary systems biology framework is proposed to integrate physical and genetic interaction networks data along with genomics to inform insights into the neurobiology of disease that can then be translated to the clinic.
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