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.

Publication Types

["Journal Article"]

Keywords

["EJC", "PAX6", "TBR2", "Upf1", "Upf3a", "Upf3b", "cell division", "neurogenesis", "p21", "p53", "progenitor cell competence"]

MeSH Terms

["Animals", "Tumor Suppressor Protein p53", "Mice", "Brain", "Mice, Knockout", "Neural Stem Cells", "Nonsense Mediated mRNA Decay", "Epistasis, Genetic", "Microcephaly", "Cell Cycle", "Cyclin-Dependent Kinase Inhibitor p21", "RNA-Binding Proteins"]

Funding

R01 GM137428 NIGMS NIH HHS (United States)

R01 NS125276 NINDS NIH HHS (United States)

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

10 data files

File	Type	Size
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

GSE220460 GSE via ncbi_elink

GEO

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

Mus musculus

4 data files

File	Type	Size
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

GSE220459 GSE via ncbi_elink

GEO

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

Mus musculus

36 data files

File	Type	Size
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

4 data files

File	Type	Size
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

GSE217735 GSE via ncbi_elink

GEO

Epigenetics CRISPRi screen in mouse neuronal progenitor cells (NPCs)

Mus musculus

6 data files

File	Type	Size
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

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