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A programmed decline in ribosome levels governs human early neurodevelopment

ABSTRACT: How reductions in ribosome biogenesis can result in tissue- and developmental-specific defects remain a mystery. Here we describe allelic variants in the ribosome biogenesis factor AIRIM/C1orf109 that are primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic, single-cell transcriptome across multiple developmental stages, and single-organoid translatome analyses, we identify a previously unappreciated drop in protein production during early brain development. We find ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time. Reduced ribosome availability more profoundly impacts the translation of specific transcripts, disrupting both survival and cell fate commitment of transitioning neuroepithelia. Enhancing mTOR activity by both genetic and pharmacologic methods suppresses the growth and developmental defects associated with intellectual disability linked variants. This work provides further evidence for the functional importance of regulated changes in global protein synthesis capacity during cellular differentiation.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Andrew Lemoff

LAB HEAD: Michael Buszczak

PROVIDER: PXD063298 | Pride | 2025-04-30

REPOSITORIES: Pride

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			Action	DRS
	ECL1_1102315.mgf	Mgf
	ECL1_1102315.pdResult	Other
	ECL1_1102315.raw	Raw

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A programmed decline in ribosome levels governs human early neurodevelopment

Project description:Many neurodevelopmental defects are linked to genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. How reductions in ribosome biogenesis can result in tissue- and developmental-specific defects remains unclear. Here we describe variants in the ribosome biogenesis factor AIRIM/C1orf109 that are primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic, single-cell RNA-seq, and single-organoid translation analyses, we identify a previously unappreciated drop in protein production during early brain development. We find ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time. Reduced ribosome availability more profoundly impacts the translation of specific transcripts, disrupting both survival and cell fate commitment of transitioning neuroepithelia. Enhancing mTOR activity suppresses the growth and developmental defects associated with AIRIM/C1orf109 variants. This work provides evidence for the functional importance of regulated changes in global protein synthesis capacity during cellular differentiation.

2025-04-26 | GSE247456 | GEO

A programmed decline in ribosome levels governs human early neurodevelopment

Project description:A programmed decline in ribosome levels governs human early neurodevelopment

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Pseudouridine-dependent ribosome biogenesis selectively regulates translation of polyglutamine proteins during Drosophila oogenesis [pulldown]

Project description:Stem cells in many systems, including Drosophila germline stem cells (GSCs), have increased ribosome biogenesis and translation during terminal differentiation. Here, we show that pseudouridylation of ribosomal RNA (rRNA) mediated by the H/ACA box is required for ribosome biogenesis and oocyte specification. Reducing ribosome levels during differentiation decreased the translation of a subset of mRNAs that are enriched for CAG repeats and encodes polyglutamine-containing proteins, including differentiation factors such as RNA-binding Fox protein 1. Moreover, ribosomes were enriched at CAG repeats within transcripts during oogenesis. Increasing TOR activity to elevate ribosome levels in H/ACA box-depleted germlines suppressed the GSC differentiation defects, whereas germlines treated with the TOR inhibitor rapamycin had reduced levels of polyglutamine-containing proteins. Thus, ribosome biogenesis and ribosome levels can control stem cell differentiation via selective translation of CAG repeat-containing transcripts.

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Pseudouridine-dependent ribosome biogenesis selectively regulates translation of polyglutamine proteins during Drosophila oogenesis [polysome-seq]

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Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice

Project description:Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the novelty of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n=43) patient cohort to date identified that hypotonia and congenital heart defects are novel prominent features. Both missense variants and putative loss-of-function variants resulted in slow growth in patient derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wildtype littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA-sequencing of patient lymphoblasts and Kmt5b-haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified novel pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems. 

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Unexpected role of a truncated ribosome-associated chloroplast trigger factor homolog serving ribosome biogenesis in plants - Data set 1 (Global proteome of wt and tig2 mutants)

Project description:Molecular chaperones are essential throughout a protein's life and act already during protein synthesis. Bacteria and chloroplasts of plant cells share the ribosome-associated chaperone trigger factor (Tig1 in plastids), facilitating maturation of emerging nascent polypeptides. While typical trigger factor chaperones employ three domains for their task, we identified a truncated form, Tig2, containing just the ribosome binding domain. Tig2 is predominantly found within higher-evolved photosynthetic species and appears to have acquired an entirely different tasks than co-translational folding. Tig2 deletion results in remarkable leaf developmental defects of cold-exposed Arabidopsis thaliana plants. Our data indicate that Tig2 functions during ribosome assembly, specifically promoting the hidden break formation within the 23S rRNA, the final step of chloroplast ribosome biogenesis. We hypothesize that Tig2 binding to the tunnel-exit surface serves protecting this sensitive surface during ribosome assembly, illustrating a fascinating concept of how similar chaperone domains have evolved for different molecular tasks.

2025-03-11 | PXD052583 | Pride

Unexpected role of a truncated ribosome-associated chloroplast trigger factor homolog serving ribosome biogenesis in plants - Data set 2: Analysis of sedimented ribosomes

2025-03-11 | PXD052586 | Pride

Unexpected role of a truncated ribosome-associated chloroplast trigger factor homolog serving ribosome biogenesis in plants - Data set 1 (Global proteome of wt and tig2 mutants)

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Unexpected role of a truncated ribosome-associated chloroplast trigger factor homolog serving ribosome biogenesis in plants - Data set 2: Analysis of sedimented ribosomes

2024-12-09 | PXD057264 | Pride

p53 activation during ribosome biogenesis regulates normal erythroid differentiation. [ChIP-Seq]

Project description:The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q- syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome biogenesis dynamics during human and murine erythropoiesis shows that ribosome biogenesis is abruptly interrupted by the drop of rDNA transcription and the collapse of ribosomal protein neo-synthesis. Its premature arrest by RNA polI inhibitor, CX-5461 targets the proliferation of immature erythroblasts. We also show that p53 is activated spontaneously or in response to CX-5461 concomitantly to ribosome biogenesis arrest, and drives a transcriptional program in which genes involved in cell cycle arrest, negative regulation of apoptosis and DNA damage response were upregulated. RNA polI transcriptional stress results in nucleolar disruption and activation of ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation are crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold of ribosome biogenesis down-regulation could be prematurely reached and together with pathological p53 activation prevents a normal expansion of erythroid progenitors.

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