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Epistatic interactions between NMD and TRP53 control progenitor cell maintenance and brain size.

Lin Lin, Jingrong Zhao, Naoto Kubota, Zhelin Li, Yi-Li Lam, Lauren P Nguyen, Lu Yang, Sheela P Pokharel, Steven M Blue, Brian A Yee, Renee Chen, Gene W Yeo, Chun-Wei Chen, Liang Chen, Sika Zheng

Neuron · 2024 · Vol. 112 (13) · pp. 2157-2176.e12

PubMed ↗ DOI ↗ PMC full text ↗

Abstract

Mutations in human nonsense-mediated mRNA decay (NMD) factors are enriched in neurodevelopmental disorders. We show that deletion of key NMD factor Upf2 in mouse embryonic neural progenitor cells causes perinatal microcephaly but deletion in immature neurons does not, indicating NMD's critical roles in progenitors. Upf2 knockout (KO) prolongs the cell cycle of radial glia progenitor cells, promotes their transition into intermediate progenitors, and leads to reduced upper-layer neurons. CRISPRi screening identified Trp53 knockdown rescuing Upf2KO progenitors without globally reversing NMD inhibition, implying marginal contributions of most NMD targets to the cell cycle defect. Integrated functional genomics shows that NMD degrades selective TRP53 downstream targets, including Cdkn1a, which, without NMD suppression, slow the cell cycle. Trp53KO restores the progenitor cell pool and rescues the microcephaly of Upf2KO mice. Therefore, one physiological role of NMD in the developing brain is to degrade selective TRP53 targets to control progenitor cell cycle and brain size.

Linked datasets 6

GSE220462 GSE · via ncbi_elink
GEO ↗

Epistatic interactions between NMD and TRP53 control progenitor cell maintenance and brain size

Mus musculus

GSE220461 GSE · via ncbi_elink
GEO ↗

Epistatic interactions between NMD and TRP53 control progenitor cell maintenance and brain size (scRNA-seq)

Mus musculus

20 data files
FileTypeSize
CRE_10x_2_CKDL210009136-1a-SI_GA_E2_HG7NTBBXX_S2_L007_I1_00… RNA-Seq 13.0 GB
CRE_IDT_1_CKDL210009136-1a-AK6102_HG7NTBBXX_L7_1.fq.gz RNA-Seq 4.0 GB
CRE_IDT_2_CKDL210009136-1a-AK6101_HG7NTBBXX_L7_1.fq.gz RNA-Seq 4.9 GB
CRE_IDT_3_CKDL210009136-1a-AK10638_HG7NTBBXX_L7_1.fq.gz RNA-Seq 3.5 GB
CRE_IDT_4_CKDL210009136-1a-AK10639_HG7NTBBXX_L7_1.fq.gz RNA-Seq 4.5 GB
GFP_10x_1_CKDL210009136-1a-SI_GA_E1_HG7NTBBXX_S1_L007_I1_00… RNA-Seq 15.4 GB
GFP_IDT_1_CKDL210009136-1a-AK10633_HG7NTBBXX_L7_1.fq.gz RNA-Seq 4.6 GB
GFP_IDT_2_CKDL210009136-1a-AK6103_HG7NTBBXX_L7_1.fq.gz RNA-Seq 4.3 GB
GFP_IDT_3_CKDL210009136-1a-AK6104_HG7NTBBXX_L7_1.fq.gz RNA-Seq 5.1 GB
GFP_IDT_4_CKDL210009136-1a-AK9608_HG7NTBBXX_L7_1.fq.gz RNA-Seq 5.2 GB
SRR22566923_GSM6805182 RNA-Seq 3.5 GB
SRR22566924_GSM6805180 RNA-Seq 4.0 GB
SRR22566925_GSM6805179 RNA-Seq 13.0 GB
SRR22566926_GSM6805181 RNA-Seq 4.9 GB
SRR22566927_GSM6805183 RNA-Seq 4.5 GB
SRR22566928_GSM6805177 RNA-Seq 5.1 GB
SRR22566929_GSM6805175 RNA-Seq 4.6 GB
SRR22566930_GSM6805174 RNA-Seq 15.4 GB
SRR22566931_GSM6805176 RNA-Seq 4.3 GB
SRR22566932_GSM6805178 RNA-Seq 5.2 GB
GSE220460 GSE · via ncbi_elink
GEO ↗

Epistatic interactions between NMD and TRP53 control progenitor cell maintenance and brain size (RNA-seq e13invivo)

Mus musculus

8 data files
FileTypeSize
Emxi_4_CKDL200155779-1a-3_HC3L5BBXX_L6_1.fq.gz RNA-Seq 4.6 GB
Emxi_5_CKDL200155779-1a-8_HC3L5BBXX_L6_1.fq.gz RNA-Seq 5.0 GB
Emxi_8_CKDL200155779-1a-10_HC3L5BBXX_L6_1.fq.gz RNA-Seq 6.0 GB
Emxi_9_CKDL200155779-1a-11_HC3L5BBXX_L6_1.fq.gz RNA-Seq 5.5 GB
SRR22566919_GSM6805173 RNA-Seq 5.5 GB
SRR22566920_GSM6805172 RNA-Seq 6.0 GB
SRR22566921_GSM6805171 RNA-Seq 5.0 GB
SRR22566922_GSM6805170 RNA-Seq 4.6 GB
GSE220459 GSE · via ncbi_elink
GEO ↗

Epistatic interactions between NMD and TRP53 control progenitor cell maintenance and brain size (RNA-seq NPC)

Mus musculus

72 data files
FileTypeSize
SRR22570245_GSM6805169 RNA-Seq 2.0 GB
SRR22570246_GSM6805169 RNA-Seq 1.8 GB
SRR22570247_GSM6805168 RNA-Seq 4.2 GB
SRR22570248_GSM6805168 RNA-Seq 3.9 GB
SRR22570249_GSM6805167 RNA-Seq 2.3 GB
SRR22570250_GSM6805167 RNA-Seq 2.1 GB
SRR22570251_GSM6805166 RNA-Seq 2.2 GB
SRR22570252_GSM6805166 RNA-Seq 2.1 GB
SRR22570253_GSM6805165 RNA-Seq 2.3 GB
SRR22570254_GSM6805164 RNA-Seq 1.9 GB
SRR22570255_GSM6805164 RNA-Seq 1.8 GB
SRR22570256_GSM6805163 RNA-Seq 2.2 GB
SRR22570257_GSM6805163 RNA-Seq 2.0 GB
SRR22570258_GSM6805165 RNA-Seq 2.1 GB
SRR22570259_GSM6805162 RNA-Seq 2.3 GB
SRR22570260_GSM6805162 RNA-Seq 2.2 GB
SRR22570261_GSM6805161 RNA-Seq 2.6 GB
SRR22570262_GSM6805161 RNA-Seq 2.4 GB
SRR22570263_GSM6805160 RNA-Seq 2.1 GB
SRR22570264_GSM6805160 RNA-Seq 2.0 GB
SRR22570265_GSM6805159 RNA-Seq 2.6 GB
SRR22570266_GSM6805159 RNA-Seq 2.4 GB
SRR22570267_GSM6805158 RNA-Seq 2.2 GB
SRR22570268_GSM6805157 RNA-Seq 2.6 GB
SRR22570269_GSM6805157 RNA-Seq 2.4 GB
SRR22570270_GSM6805156 RNA-Seq 2.6 GB
SRR22570271_GSM6805156 RNA-Seq 2.4 GB
SRR22570272_GSM6805158 RNA-Seq 2.0 GB
SRR22570273_GSM6805155 RNA-Seq 2.1 GB
SRR22570274_GSM6805155 RNA-Seq 1.9 GB
SRR22570275_GSM6805154 RNA-Seq 2.7 GB
SRR22570276_GSM6805154 RNA-Seq 2.5 GB
SRR22570277_GSM6805153 RNA-Seq 2.7 GB
SRR22570278_GSM6805153 RNA-Seq 2.5 GB
SRR22570279_GSM6805152 RNA-Seq 2.1 GB
SRR22570280_GSM6805152 RNA-Seq 1.9 GB
UC_3_CKDL220004752-1a-3_HHJT3BBXX_L8_1.fq.gz RNA-Seq 1.9 GB
UC_3_CKDL220004752-1a-3_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.1 GB
UC_4_CKDL220004752-1a-11_HHJT3BBXX_L8_1.fq.gz RNA-Seq 2.5 GB
UC_4_CKDL220004752-1a-11_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.7 GB
UC_5_CKDL220004752-1a-23_HHJT3BBXX_L8_1.fq.gz RNA-Seq 2.5 GB
UC_5_CKDL220004752-1a-23_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.7 GB
UC_6_CKDL220004752-1a-4_HHJT3BBXX_L8_1.fq.gz RNA-Seq 1.9 GB
UC_6_CKDL220004752-1a-4_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.1 GB
UC_8_CKDL220004752-1a-12_HHJT3BBXX_L8_1.fq.gz RNA-Seq 2.4 GB
UC_8_CKDL220004752-1a-12_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.6 GB
UC_9_CKDL220004752-1a-16_HHJT3BBXX_L8_1.fq.gz RNA-Seq 2.4 GB
UC_9_CKDL220004752-1a-16_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.6 GB
UM_3_CKDL220004752-1a-1_HHJT3BBXX_L8_1.fq.gz RNA-Seq 2.0 GB
UM_3_CKDL220004752-1a-1_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.2 GB
UM_4_CKDL220004752-1a-10_HHJT3BBXX_L8_1.fq.gz RNA-Seq 2.4 GB
UM_4_CKDL220004752-1a-10_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.6 GB
UM_5_CKDL220004752-1a-22_HHJT3BBXX_L8_1.fq.gz RNA-Seq 2.0 GB
UM_5_CKDL220004752-1a-22_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.1 GB
UM_6_CKDL220004752-1a-2_HHJT3BBXX_L8_1.fq.gz RNA-Seq 2.4 GB
UM_6_CKDL220004752-1a-2_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.6 GB
UM_8_CKDL220004752-1a-7_HHJT3BBXX_L8_1.fq.gz RNA-Seq 2.2 GB
UM_8_CKDL220004752-1a-7_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.3 GB
UM_9_CKDL220004752-1a-15_HHJT3BBXX_L8_1.fq.gz RNA-Seq 2.0 GB
UM_9_CKDL220004752-1a-15_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.2 GB
UP_C3_CKDL220004752-1a-9_HHJT3BBXX_L8_1.fq.gz RNA-Seq 1.8 GB
UP_C3_CKDL220004752-1a-9_HHJWLBBXX_L1_1.fq.gz RNA-Seq 1.9 GB
UP_C4_CKDL220004752-1a-21_HHJT3BBXX_L8_1.fq.gz RNA-Seq 2.1 GB
UP_C4_CKDL220004752-1a-21_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.3 GB
UP_C5_CKDL220004752-1a-27_HHJT3BBXX_L8_1.fq.gz RNA-Seq 2.1 GB
UP_C5_CKDL220004752-1a-27_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.2 GB
UP_C6_CKDL220004752-1a-6_HHJT3BBXX_L8_1.fq.gz RNA-Seq 2.1 GB
UP_C6_CKDL220004752-1a-6_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.3 GB
UP_C8_CKDL220004752-1a-14_HHJT3BBXX_L8_1.fq.gz RNA-Seq 3.9 GB
UP_C8_CKDL220004752-1a-14_HHJWLBBXX_L1_1.fq.gz RNA-Seq 4.2 GB
UP_C9_CKDL220004752-1a-19_HHJT3BBXX_L8_1.fq.gz RNA-Seq 1.8 GB
UP_C9_CKDL220004752-1a-19_HHJWLBBXX_L1_1.fq.gz RNA-Seq 2.0 GB
GSE253825 GSE · via ncbi_elink
GEO ↗

Nonsense-mediated mRNA decay counteracts TRP53 to maintain the progenitor cell pool for brain development (snRNA-seq_e15invivo)

Mus musculus

8 data files
FileTypeSize
Ctrl_3_AACCGTAA_S1_L001_R1_001.fastq.gz RNA-Seq 29.4 GB
Ctrl_3_TCGGCGTC_S1_L001_R1_001.fastq.gz RNA-Seq 30.8 GB
KO_1_CTAAACGG_S1_L001_R1_001.fastq.gz RNA-Seq 27.4 GB
KO_1_GGTTTACT_S1_L001_R1_001.fastq.gz RNA-Seq 29.0 GB
SRR27674088_GSM8028391 RNA-Seq 27.4 GB
SRR27674089_GSM8028391 RNA-Seq 29.0 GB
SRR27674090_GSM8028390 RNA-Seq 29.4 GB
SRR27674091_GSM8028390 RNA-Seq 30.8 GB
GSE217735 GSE · via ncbi_elink
GEO ↗

Epigenetics CRISPRi screen in mouse neuronal progenitor cells (NPCs)

Mus musculus

12 data files
FileTypeSize
SRR22255533_GSM6725607 OTHER 96.0 MB
SRR22255534_GSM6725606 OTHER 99.0 MB
SRR22255535_GSM6725605 OTHER 101.0 MB
SRR22255536_GSM6725604 OTHER 106.0 MB
SRR22255537_GSM6725603 OTHER 107.0 MB
SRR22255538_GSM6725602 OTHER 141.0 MB
SZ20210524JZ_msEpiCRISPRi_NPC_Upf2KO_05_Cre_S51_L999_R1_001… OTHER 141.1 MB
SZ20210524JZ_msEpiCRISPRi_NPC_Upf2KO_05_GFP_S50_L999_R1_001… OTHER 107.9 MB
SZ20210524JZ_msEpiCRISPRi_NPC_Upf2KO_05_sgRNA_S49_L999_R1_0… OTHER 106.2 MB
SZ20210524JZ_msEpiCRISPRi_NPC_Upf2KO_50_Cre_S54_L999_R1_001… OTHER 101.3 MB
SZ20210524JZ_msEpiCRISPRi_NPC_Upf2KO_50_GFP_S53_L999_R1_001… OTHER 100.0 MB
SZ20210524JZ_msEpiCRISPRi_NPC_Upf2KO_50_sgRNA_S52_L999_R1_0… OTHER 96.8 MB

Potentially related datasets 7

These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.

Accession Source Title
GSE210437 GSE · GEO GEO ↗ Enhanced CLIP (eCLIP) identified differential UPF1 binding sites in mouse neural progenitor cells (NPCs) samples
GSE107122 GSE · GEO GEO ↗ Developmental emergence of adult neural stem cells as revealed by single cell transcriptional profiling
GSE220460 GSE · GEO GEO ↗ Epistatic interactions between NMD and TRP53 control progenitor cell maintenance and brain size (RNA-seq e13invivo)
GSE217735 GSE · GEO GEO ↗ Epigenetics CRISPRi screen in mouse neuronal progenitor cells (NPCs)
GSE220459 GSE · GEO GEO ↗ Epistatic interactions between NMD and TRP53 control progenitor cell maintenance and brain size (RNA-seq NPC)
GSE253825 GSE · GEO GEO ↗ Nonsense-mediated mRNA decay counteracts TRP53 to maintain the progenitor cell pool for brain development (snRNA-seq_e15invivo)
GSE220461 GSE · GEO GEO ↗ Epistatic interactions between NMD and TRP53 control progenitor cell maintenance and brain size (scRNA-seq)

Analysis pipelines 8

Pipeline Assay Steps Dataset
GSE107122 RNA-seq Data Processing geo_data_processing RNA-seq 4 GSE107122
GSE210437 eCLIP Data Processing geo_data_processing eCLIP 9 GSE210437
GSE217735 Data Processing geo_data_processing — 2 GSE217735
GSE220459 RNA-seq Data Processing geo_data_processing RNA-seq 2 GSE220459
GSE220460 RNA-seq Data Processing geo_data_processing RNA-seq 2 GSE220460
GSE220461 RNA-seq Data Processing geo_data_processing RNA-seq 1 GSE220461
GSE220462 Data Processing geo_data_processing — 2 GSE220462
GSE253825 RNA-seq Data Processing geo_data_processing RNA-seq 1 GSE253825
Funding 2 grants
Grant Funder
R01 GM137428 NIGMS NIH HHS (United States)
R01 NS125276 NINDS NIH HHS (United States)