Primordial dwarfism gene maintains Lin28 expression to safeguard embryonic stem cells from premature differentiation.
Primordial dwarfism (PD) is characterized by global growth failure, both during embryogenesis and postnatally. Loss-of-function germline mutations in La ribonucleoprotein domain family, member 7 (LAPR7) have recently been linked to PD. Paradoxically, LARP7 deficiency was previously assumed to be associated with increased cell growth and proliferation via activation of positive transcription elongation factor b (P-TEFb). Here, we show that Larp7 deficiency likely does not significantly increase P-TEFb activity. We further discover that Larp7 knockdown does not affect pluripotency but instead primes embryonic stem cells (ESCs) for differentiation via downregulation of Lin28, a positive regulator of organismal growth. Mechanistically, we show that Larp7 interacts with a poly(A) polymerase Star-PAP to maintain Lin28 mRNA stability. We propose that proper regulation of Lin28 and PTEFb is essential for embryonic cells to achieve a sufficient number of cell divisions prior to differentiation and ultimately to maintain proper organismal size.
Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resources and Eco-Environment, and State Key Laboratory of Biotherapy, College of Life Sciences, Sichuan University, Chengdu 610064, Sichuan, China.
Qian
Q
Dai
Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resources and Eco-Environment, and State Key Laboratory of Biotherapy, College of Life Sciences, Sichuan University, Chengdu 610064, Sichuan, China.
Guangxin
G
Luan
Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resources and Eco-Environment, and State Key Laboratory of Biotherapy, College of Life Sciences, Sichuan University, Chengdu 610064, Sichuan, China.
Li
L
Deng
Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resources and Eco-Environment, and State Key Laboratory of Biotherapy, College of Life Sciences, Sichuan University, Chengdu 610064, Sichuan, China.
Tingjun
T
Lei
Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resources and Eco-Environment, and State Key Laboratory of Biotherapy, College of Life Sciences, Sichuan University, Chengdu 610064, Sichuan, China.
Han
H
Kang
Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resources and Eco-Environment, and State Key Laboratory of Biotherapy, College of Life Sciences, Sichuan University, Chengdu 610064, Sichuan, China.
Xu
X
Song
Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resources and Eco-Environment, and State Key Laboratory of Biotherapy, College of Life Sciences, Sichuan University, Chengdu 610064, Sichuan, China.
Yujun
Y
Zhang
Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resources and Eco-Environment, and State Key Laboratory of Biotherapy, College of Life Sciences, Sichuan University, Chengdu 610064, Sichuan, China.
Zhi-Xiong
ZX
Xiao
Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resources and Eco-Environment, and State Key Laboratory of Biotherapy, College of Life Sciences, Sichuan University, Chengdu 610064, Sichuan, China. Electronic address: liqintong@scu.edu.cn.
Qintong
Q
Li
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004392:Dwarfism / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000075065:Elongin; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D011062:Polynucleotide Adenylyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012261:Ribonucleoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D000075065:Elongin; C528908:Larp7 protein, human; C488352:Lin-28 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D012261:Ribonucleoproteins; D014157:Transcription Factors; D011062:Polynucleotide Adenylyltransferase