Purpose:To study a non-redundant role of Tcf12 in retinal health. Methods:A loss-of-function mutation in Tcf12 was identified by applying optical coherence tomography (OCT) to a forward genetic pipeline. CRISPR/Cas9-generated Tcf12ra/ra mice, expressing a replacement allele ("ra") were used to validate the findings from the mutagenesis screen. Retinal morphology was assessed using OCT, fundus photography, histology, and immunohistochemistry. Retinal function was evaluated by electroretinography (ERG). Bulk RNA sequencing and proteomic analyses were performed, with select targets validated by RT-qPCR and immunoblotting. Results:Tcf12ra/ra mice exhibited outer nuclear layer thinning on OCT, which was confirmed by histology. Fundus imaging revealed age-dependent accumulation of retinal fundus spots. Subretinal accumulation of Iba1⁺/Tmem119⁺ cells was observed, many of which stained positively for Gal3, suggestive of activated resident microglia. ERG deficits were noticed at 12 to 15 months of age in Tcf12ra/ra mice. Transcriptomic and proteomic profiling using two independent pathway analyses identified dysregulated pathways related to protein and RNA metabolism, mitochondrial and energy metabolism, cell cycle, signal transduction, cellular response to stimuli, and inflammation. RT-qPCR results showed upregulation of Tmem233 and downregulation of Doc2b, Alpk2, Agr2, and Apobec2 in Tcf12ra/ra retinas. Western blot analysis demonstrated upregulation of Selenbp1 and downregulation of Neurod1 and Faah in Tcf12ra/ra retinas. Conclusions:Deficiency in Tcf12 induces early-onset retinal structural alterations, and late-onset subretinal microglial activation and functional decline. Widespread dysregulation in metabolic and signaling pathways was documented in transcriptomic and proteomic analyses. These findings establish Tcf12 as a key contributor to retinal development and homeostasis.

Neurodegenerative tauopathies, including Alzheimer’s disease, appear to be driven by propagation of tau assemblies, which must access the cytoplasm to recruit monomer and self-replicate, a process termed “seeding.” The prevailing model holds that tau seeds enter cells via macropinocytosis and reach the cytosol through lysosomal rupture or micro-perforation. Our findings revise this model by revealing that endocytosis is not required for seeding. Using genome-scale CRISPR screening, we identified multiple v-ATPase components whose loss reduced tau uptake (measured by flow cytometry) yet paradoxically increased seeding (measured by FRET biosensors). Acute v-ATPase inhibition with bafilomycin A1 produced the same effect in v2L tau biosensors and iPSC-derived neurons. Among regulators of endosome maturation, dominant-negative Rab5a decreased internalization while enhancing cytoplasmic templating. Cholesterol depletion produced identical results. Strikingly, transient hypothermia eliminated virtually all detectable tau uptake and dramatically increased seeding, without affecting subsequent tau monomer or aggregate degradation. We conclude that efficient endolysosomal trafficking does not appear to be required for cytoplasmic seeding under the conditions studied here. Across diverse perturbations, reduced endolysosomal flux consistently enhanced tau seeding, consistent with prior work indicating that most internalized aggregates are routed toward degradation rather than amplification. To seed effectively, tau must cross the plasma or vesicular membranes into the cytoplasm. We have found that proper endolysosomal trafficking suppresses cytoplasmic tau seeding, as all perturbations augmented this process. These findings reframe the role of the endolysosomal system in tau seeding and identify membrane transit rather than macropinocytosis itself as a critical gateway to cytoplasmic tau amplification.

INTRODUCTION:Effective therapies are needed for patients with NSCLC with HER2-mutant tumors who progress on the HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd), a standard-of-care treatment. A greater understanding of mechanisms mediating acquired T-DXd resistance and whether these tumors could benefit from HER2 tyrosine kinase inhibitors (TKIs) is needed. METHODS:Using preclinical models of acquired T-DXd resistance, LentiMutate scanning mutagenesis, and clinical analyses, we investigated mechanisms mediating acquired resistance to T-DXd and assessed the impact of each of these resistance mechanisms on cross-resistance to alternative HER2-targeting approaches. RESULTS:We determined that acquired resistance to T-DXd could occur through multiple mechanisms including payload resistance which could be mediated by SFLN11 loss and copy number gains in the efflux pump ABCC1/MRP1. Moreover, T-DXd resistance could be mediated by secondary HER2 extracellular mutations in domain IV, the trastuzumab binding site. Tumor cells with acquired payload resistance or domain IV mutations maintained HER2 signaling and remained sensitive to HER2 TKIs, including zongertinib or poziotinib. Likewise, patients with HER2-mutant NSCLC treated with poziotinib demonstrated similar response rates regardless of prior T-DXd. CONCLUSIONS:In patients with HER2-mutant NSCLC, loss of HER2 is not a universal mechanism of T-DXd resistance. Collectively, these data highlight multiple mechanisms of resistance to T-DXd that do not result in loss of HER2 TKI responsiveness.

Abstract Introduction Thymus organogenesis depends on coordinated communication between stromal and hematopoietic cells. We found that thymic mesenchyme contains a specialized stromal subset (CD45⁻Ter119⁻PDGFRA+PDGFRB+CD90+) distinct from mesenchyme of the pharyngeal, submandibular, tongue, and lung regions, which uniquely signals to thymic epithelial cells. Methods We compared stromal competence across organs using flow cytometry, single-cell transcriptomics, and recombinant reaggregate thymic organoid culture (ReRTOC). Pharmacologic reprogramming was tested in Tbx1neo2/neo2 embryos (∼36% normal Tbx1), a model of 22q11.2 deletion syndrome, using the FDA-approved drug Minoxidil. Results ReRTOC assays showed that pharyngeal and submandibular mesenchyme retain partial ability (∼60% thymic growth) to support epithelial expansion and thymopoiesis, revealing inherent plasticity. In Tbx1neo2/neo2 mutants, mesenchyme exhibited a shift from Bmp4 to Bmp5—Sox9 signaling, driving chondrogenic differentiation (Col2a1, Col9a1, Col11a1), loss of stromal organization, and reduced vascular branching with a lower SMA/Cx40 ratio. Minoxidil restored Bmp4 activity, suppressed Sox9/Bmp5 expression, and normalized thymic size and vascular complexity. CellChat analysis of wild-type thymic stroma revealed perivascular mesenchymal subsets acting as dominant signaling hubs, communicating with endothelial cells through the LAMININ, SPP1, BSP, and WNT pathways, which maintain basement membrane stability and endothelial anchoring. Conclusion Our results demonstrate that mesenchymal—endothelial communication is essential for thymic vascular patterning and that targeted mesenchymal reprogramming–through pharmacological or growth factor cues–can restore thymic vascularization and function, even during aging. Funding Source This work was supported, in part by grants from the National Institutes of Health Grant R01 AI114523 (Nicolai S.C. van Oers) and Jeffrey Modell Foundation (Christian A. Wysocki) Topic Categories Hematopoiesis and Immune System Development (HEM)

Anti-HER2 antibodies are effective but often lead to resistance in patients with HER2+ breast cancer. Here, we report an epigenetic crosstalk with aberrant glycerophospholipid metabolism and inflammation as a key resistance mechanism of anti-HER2 therapies in HER2+ breast cancer. Histone reader ZMYND8 specifically confers resistance to cancer cells against trastuzumab and/or pertuzumab. Mechanistically, ZMYND8 enhances cPLA2α expression in resistant tumor cells through inducing c-Myc. cPLA2α inactivates phosphatidylcholine-specific phospholipase C to inhibit phosphatidylcholine breakdown into diacylglycerol, which diminishes protein kinase C activity leading to interleukin-27 secretion. Supplementation with interleukin-27 protein counteracts cPLA2α loss to reinforce trastuzumab resistance in HER2+ tumor cells and patient-derived organoids. Upregulation of ZMYND8, c-Myc, cPLA2α, and IL-27 is prevalent in HER2+ breast cancer patients following HER2-targeted therapies. Targeting c-Myc or cPLA2α effectively overcomes anti-HER2 therapy resistance in patient-derived xenografts. Collectively, this study uncovers a druggable signaling cascade that drives resistance to HER2-targeted therapies in HER2+ breast cancer.

22q11.2 deletion syndrome causes thymic hypoplasia. In an embryonic mouse model, Sox9-expressing chondrocytes expanded in the hypoplastic thymuses. A drug screen identified minoxidil as a therapeutic that restored thymus growth and limited the overproduction of collagens and ECM proteins when administered in pregnant mice.

Thymic hypoplasia, hypoparathyroidism, and cardiac defects are common congenital malformations caused by 22q11.2 deletion syndrome (22q11.2DS; aka DiGeorge syndrome). Thymus hypoplasia reduces peripheral T cell numbers, leading to more frequent infections. We report that embryonic hypoplastic thymuses from mouse models of 22q11.2DS (Tbx1neo2/neo2) have distinct mesenchymal cell subsets, including an expansion of Sox9+ chondrocytes. Chondrocytes produce collagens and extracellular matrix (ECM) proteins, which can affect thymus size and vascularization. Two compounds, minoxidil and PGE2, restored growth for Tbx1neo2/neo2 embryonic thymuses when administered to pregnant mice prior to formation of the thymic anlage. The dysregulation of the mesenchymal and endothelial transcriptomes was corrected with minoxidil in Tbx1neo2/neo2 thymuses. This was confirmed by the diminished expression of Sox9-driven type II, IX, and XI cartilaginous collagens and other ECM proteins. Furthermore, the location of parathyroids was corrected in Tbx1neo2/neo2 embryos. In summary, these findings reveal that targeting prenatal mesenchymal differentiation can correct multiple congenital anomalies in mouse models of 22q11.2DS.

Functional inactivation of tumor suppressor genes drives cancer initiation, progression, and treatment responses. Most tumor suppressor genes are inactivated through 1 of 2 well-characterized mechanisms: DNA-level mutations, such as point mutations or deletions, and promoter DNA hypermethylation. Here, we report a distinct third mechanism of tumor suppressor inactivation based on alterations to the histone rather than DNA code. We demonstrated that PAX2 is an endometrial tumor suppressor recurrently inactivated by a distinct epigenetic reprogramming event in more than 80% of human endometrial cancers. Integrative transcriptomic, epigenomic, 3D genomic, and machine learning analyses showed that PAX2 transcriptional downregulation is associated with replacement of open/active chromatin features (H3K27ac/H3K4me3) with inaccessible/repressive chromatin features (H3K27me3) in a framework dictated by 3D genome organization. The spread of the repressive H3K27me3 signal resembled a pearl necklace, with its length modulated by cohesin loops, thereby preventing transcriptional dysregulation of neighboring genes. This mechanism, involving the loss of a promoter-proximal superenhancer, was shown to underlie transcriptional silencing of PAX2 in human endometrial cancers. Mouse and human preclinical models established PAX2 as a potent endometrial tumor suppressor. Functionally, PAX2 loss promoted endometrial carcinogenesis by rewiring the transcriptional landscape via global enhancer reprogramming. The discovery that most endometrial cancers originate from a recurring epigenetic alteration carries profound implications for their diagnosis and treatment.

Malaria treatments are compromised by drug resistance, creating an urgent need to discover new drugs. We used a phenotypic high-throughput screening (HTS) platform to identify new antimalarials, uncovering three related pyrrole-, indole-, and indoline-based series with a shared α-azacyclic acetamide core. These compounds showed fast-killing activity on asexual blood-stage Plasmodium falciparum parasites, were not cytotoxic, and disrupted parasite intracellular pH and Na + regulation similarly to cipargamin (KAE609), a clinically advanced inhibitor of the P. falciparum Na + pump ( Pf ATP4). Pf ATP4 is localized to the parasite plasma membrane and is essential for maintaining a low cytosolic Na + concentration. Resistance selections on P. falciparum parasites with two α-azacyclic acetamide analogs identified mutations in Pf ATP4, and cross-resistance was observed across the α-azacyclic acetamides and KAE609, confirming Pf ATP4 as the target. Pf ATP4 is a well-established antimalarial target, and identification of additional Pf ATP4 inhibitors provides alternative avenues to disrupt its function.

Gain of plasticity and loss of MHC-II enable tumor cells to evade immune surveillance, contributing to tumor development. Here, we showed that the transcriptional corepressor RCOR2 is a key factor that integrates two epigenetic programs surveilling tumor plasticity and immunogenicity. RCOR2 was upregulated predominantly in tumor cells and promoted tumor development in mice through reducing tumor cell death by CD4+CD8+ T cells and inducing cancer stemness. Mechanistically, RCOR2 repressed RNF43 expression through LSD1-mediated demethylation of histone H3 at lysine 4 to induce activation of Wnt/β-catenin and tumor stemness. Simultaneously, RCOR2 inhibited CIITA expression through HDAC1/2-mediated deacetylation of histone H4 at lysine 16, leading to MHC-II silencing in tumor cells and subsequent impairment of CD4+CD8+ T cell immunosurveillance, thereby promoting immune evasion. RCOR2 loss potentiated anti-PD-1 therapy in mouse models of cancer and correlated with better response to anti-PD-1 therapy in human patients. Collectively, these findings uncover a "two birds with one stone" effect for RCOR2, highlighting its potential as a valuable target for improved cancer therapy.

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 sequencing and single-organoid translation analyses, we identify a previously unappreciated drop in protein production during early brain development. We find that 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.

Thymic hypoplasia, hypoparathyroidism, cardiac defects, and/or dysmorphic facial features are frequent congenital malformations resulting from chromosome 22q11.2 deletion syndrome (22q11.2DS; aka DiGeorge syndrome). Thymus hypoplasia results in reduced peripheral T cells, with patients suffering from more frequent and severe infections. Embryonic thymuses from mouse models of 22q11.2DS (Tbx1neo2/neo2) are smaller than controls. Such thymuses had a distinct mesenchymal cell subset representation, altered transcriptomes, and elevated levels of collagens and extracellular matrix (ECM) proteins. We report that the administration of minoxidil or PGE2 to pregnant mice restored thymic tissue growth in Tbx1neo2/neo2 embryos. The drugs normalized the embryonic thymic mesenchymal subcluster representation, their respective transcriptomes, and corrected the underdeveloped vasculature. Importantly, the restoration of thymic growth matched the reduced number of perivascular/chondrogenic-derived mesenchymal subsets. Comparative transcriptomic, gene expression, and immunofluorescence analyses revealed elevated expression levels of a trio of Sox family transcription factors (Sox5, 6, and 9) in the small thymuses. Sox9 positively regulates the expression type II, IX, and X cartilaginous collagens and other ECM proteins, which are elevated in the hypoplastic lobes. Notably, minoxidil or PGE2 treatments reduced Sox9 expression and the correspondingly regulated collagens. This treatment also corrected the location of the parathyroids, indicating that a therapeutic drug treatment can correct several congenital defects associated with 22q11.2DS.

Objective: An intronic cytosine-thymine-guanine (CTG) triplet repeat expansion in the transcription factor 4 gene (TCF4) gene (CTG18.1) confers significant risk for the development of Fuchs' endothelial corneal dystrophy (FECD). The objective of this study was to conduct an unbiased survey of the CTG18.1 repeat expansion allele frequencies in a multiethnic population-based cohort from the United States and in global populations. Design: Cross-sectional study. Subjects: Dallas Heart Study (DHS) cohort including 1599 African Americans (AAs), 1028 European Americans (EAs), and 458 Latinos; 2500 individuals from the 1000 Genomes Project (1KGP) sampled from 26 populations across 5 continents. Methods: We genotyped the CTG18.1 short tandem repeat (STR) in DHS using targeted polymerase chain reaction amplification followed by fragment analysis. We also inferred the CTG18.1 repeat genotype based on short-read whole-genome sequencing in 1KGP using the computational tool ExpansionHunter. Main Outcome Measures: The prevalence of an expanded CTG18.1 allele with > 40 repeats was determined in United States and global populations. Results: The carrier rates of the expanded allele were 3.1%, 8.1%, and 3.3% in AAs, EAs, and Latinos, respectively, in the DHS, and 2.7%, 9.5%, 5.2%, 7.2%, and 5.2% in the African (AFR), European (EUR), East Asian, South Asian, and admixed American continental populations, respectively, in the 1KGP. The distributions of the CTG18.1 repeat in DHS and in 1KGP are similar. The median repeat length was-17 with the interquartile range between 12 and 23 in the DHS populations. The median repeat length was-19 in all the 1KGP populations with the interquartile range between 13 and 26. The highest prevalence of the expanded allele carriers ranging from 12.1% to 12.5% was observed in some EUR and admixed American subpopulations. The frequency of expanded alleles carriers was absent or low (0%e1.9%) in subpopulations of West Africa but was present at 6.2% in a Kenyan subpopulation in East Africa. Conclusions: The TCF4 repeat expansion is most prevalent in people of EUR ancestry and least in AFR ancestry, which is consistent with FECD prevalence. The expanded TCF4 CTG18.1 allele is the most common disease-causing STR in humans with worldwide implications for corneal disease. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. Ophthalmology Science 2025;5:100611 (c) 2024 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Activated microglia have been implicated in the pathogenesis of age-related macular degeneration (AMD), diabetic retinopathy, and other neurodegenerative and neuroinflammatory disorders, but our understanding of the mechanisms behind their activation is in infant stages. With the goal of identifying novel genes associated with microglial activation in the retina, we applied a semiquantitative fundus spot scoring scale to an unbiased, state-of-the-science mouse forward genetics pipeline. A mutation in the gene encoding the E3 ubiquitin ligase Herc3 led to prominent accumulation of fundus spots. CRISPR mutagenesis was used to generate Herc3-/- mice, which developed prominent accumulation of fundus spots and corresponding activated Iba1 + /CD16 + subretinal microglia, retinal thinning on OCT and histology, and functional deficits by Optomotory and electrophysiology. Bulk RNA sequencing identified activation of inflammatory pathways and differentially expressed genes involved in the modulation of microglial activation. Thus, despite the known expression of multiple E3 ubiquitin ligases in the retina, we identified a non-redundant role for Herc3 in retinal homeostasis. Our findings are significant given that a dysregulated ubiquitin–proteasome system (UPS) is important in prevalent retinal diseases, in which activated microglia appear to play a role. This association between Herc3 deficiency, retinal microglial activation and retinal degeneration merits further study.

Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen in C57BL/6J mice, we discovered a mutation in host H2-Aa that caused strong immune-mediated resistance to mouse melanomas. H2-Aa encodes an MHC class II α chain, and its absence in C57BL/6J mice eliminates all MHC-II expression. H2-Aa deficiency, specifically in dendritic cells (DC), led to a quantitative increase in type 2 conventional DC (cDC2) and a decrease in cDC1. H2-Aa-deficient cDC2, but not cDC1, were essential for melanoma suppression and effectively cross-primed and recruited CD8 T cells into tumors. Lack of T regulatory cells, also observed in H2-Aa deficiency, contributed to melanoma suppression. Acute disruption of H2-Aa was therapeutic in melanoma-bearing mice, particularly when combined with checkpoint inhibition, which had no therapeutic effect by itself. Our findings suggest that inhibiting MHC-II may be an effective immunotherapeutic approach to enhance immune responses to cancer.

Objective An intronic CTG triplet repeat expansion in the transcription factor 4 gene (TCF4) gene (CTG18.1) confers significant risk for the development of Fuchs’ endothelial corneal dystrophy (FECD). The objective of this study was to conduct an unbiased survey of the CTG18.1 repeat expansion allele frequencies in a multi-ethnic, population-based cohort from the United States and in global populations. Design Cross-sectional study Subjects Dallas Heart Study (DHS) cohort including 1,599 African Americans (AAs), 1,028 European Americans (EAs), and 458 Latinos; 2,500 individuals from the 1000 Genomes Project (1KGP) sampled from 26 populations across 5 continents. Methods We genotyped the CTG18.1 short tandem repeat in DHS using targeted polymerase chain reaction amplification followed by fragment analysis. We also inferred the CTG18.1 repeat genotype based on short-read whole-genome sequencing in 1KGP using the computational tool ExpansionHunter. Main Outcome Measures The prevalence of an expanded CTG18.1 allele with ≥40 repeats was determined in U.S. and global populations. Results The carrier rates of the expanded allele were 3.1%, 8.1%, and 3.3% in AAs, EAs, and Latinos, respectively, in the DHS, and 2.7%, 9.5%, 5.2%, 7.2%, and 5.2% in the African (AFR), European (EUR), East Asian (EAS), South Asian (SAS), and admixed American (AMR) continental populations, respectively, in the 1KGP. The distributions of the CTG18.1 repeat in DHS and in 1KGP are similar. The median repeat length was ∼17 with the interquartile range (IQR) between 12 and 23 in the DHS populations. The median repeat length was ∼19 in all the 1KGP populations with the IQR between 13 and 26. The highest prevalence of the expanded allele carriers ranging from 12.1% to 12.5% was observed in some EUR and AMR subpopulations. The frequency of expanded alleles carriers was absent or low (0 - 1.9%) in subpopulations of East Africa but was present at 6.2% in a Kenyan subpopulation in West Africa. Conclusions The TCF4 repeat expansion is most prevalent in people of European ancestry and least in African ancestry, which is consistent with FECD prevalence. The expanded TCF4 CTG18.1 allele is the most common disease-causing short tandem repeat in humans with worldwide implications for corneal disease.

Breast cancer stem cells (BCSCs) mitigate oxidative stress to maintain their viability and plasticity. However, the regulatory mechanism of oxidative stress in BCSCs remains unclear. We recently found that the histone reader ZMYND8 was upregulated in BCSCs. Here, we showed that ZMYND8 reduced ROS and iron to inhibit ferroptosis in aldehyde dehydrogenase-high (ALDHhi) BCSCs, leading to BCSC expansion and tumor initiation in mice. The underlying mechanism involved a two-fold posttranslational regulation of nuclear factor erythroid 2-related factor 2 (NRF2). ZMYND8 increased stability of NRF2 protein through KEAP1 silencing. On the other hand, ZMYND8 interacted with and recruited NRF2 to the promoters of antioxidant genes to enhance gene transcription in mammospheres. NRF2 phenocopied ZMYND8 to enhance BCSC stemness and tumor initiation by inhibiting ROS and ferroptosis. Loss of NRF2 counteracted ZMYND8's effects on antioxidant genes and ROS in mammospheres. Interestingly, ZMYND8 expression was directly controlled by NRF2 in mammospheres. Collectively, these findings uncover a positive feedback loop that amplifies the antioxidant defense mechanism sustaining BCSC survival and stemness.

Many neurodevelopmental defects are linked to perturbations in genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. However, how reductions in ribosome biogenesis can result in tissue and developmental specific defects remains a mystery. Here we describe new allelic variants in the ribosome biogenesis factor AIRIM primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic analysis, single-cell transcriptome analysis across multiple developmental stages, and single organoid translatome analysis, we identify a previously unappreciated mechanism linking changes in ribosome levels and the timing of cell fate specification 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 approaches ameliorates the growth and developmental defects associated with intellectual disability linked variants, identifying potential treatment options for specific brain ribosomopathies. This work reveals the cellular and molecular origins of protein synthesis defect-related disorders of human brain development. Highlights:AIRIM variants reduce ribosome levels specifically in neural progenitor cells. Inappropriately low ribosome levels cause a transient delay in radial glia fate commitment.Reduced ribosome levels impair translation of a selected subset of mRNAs.Genetic and pharmacologic activation of mTORC1 suppresses AIRIM-linked phenotypes.