Cell Proliferation >

2024 , Vol. 57 >Issue 5: 0

DOI: https://doi.org/10.1111/cpr.13580

Transcription factor PBX4 regulates limb development and haematopoiesis in mice

  • Yan Ning 1,2,3,4 ,
  • Shuguang Duo 1,2,3 ,
  • Xiwen Lin 1,2,3 ,
  • Hongbo Zhang 5 ,
  • Jifeng Fei 6 ,
  • Bao Zhang 5,7 ,
  • Yanyun Zeng 6 ,
  • Dan Xie 1,2,3,4 ,
  • Jian Chen 1,2,3 ,
  • Xiaowei Liu 1,2,3,4 ,
  • Chunsheng Han , 1,2,3,4
Expand
  • 1. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
  • 2. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
  • 3. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
  • 4. Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China
  • 5. The Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
  • 6. Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
  • 7. Medical College of Jiaying University, Meizhou, China
hancs@ioz.ac.cn

Received date: 01 Sep 2023

Revised date: 25 Oct 2023

Accepted date: 07 Nov 2023

Copyright

2024 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.
Fold

Abstract

The mammalian Pre-B cell leukaemia transcription factors 1–4 (PBX1-4) constitutes the PBC class of the homeodomain (HD)-containing proteins, which play important roles in diverse developmental processes. The functions and the underlying molecular mechanisms of PBX1-3 but not PBX4 have been extensively studied, and they have been reported to direct essential morphogenetic processes and organogenesis. In the present study, we generated knockin mice of FLAG-tagged PBX4 and the Pbx4 knockout (KO) mice and carried out in-depth characterisation of PBX4 expression and function. PBX4 was initially detected only in the testis among several organs of the adult mice and was expressed in spermatocytes and spermatids. However, no abnormality in spermatogenesis, but growth retardation and premature death after birth were observed in most adult Pbx4 KO mice. These animals were inactive and had shorter hindlimbs and lower numbers of reticulocytes and lymphocytes, probably caused by abnormalities at earlier developmental stages. Pbx4 mRNAs were indeed detected in several embryonic cell types related to limb development by in situ hybridisation and single-cell RNA-sequencing analysis. Pbx4 protein was also detected in the bone marrow of adult mice with a lower level compared with that in the testis. PBX4 preferentially binds to the promoters of a large number of genes including those for other HD-containing proteins and ribosomal proteins whose mutations are related to anaemia. PBX4-binding sites are enriched in motifs similar to those of other HD-containing proteins such as PKNOX1 indicating that PBX4 may also act as a co-transcription factor like other PBC proteins. Together, these results show that PBX4 participates in limb development and haematopoiesis while its function in spermatogenesis has not been revealed by gene KO probably due to the complementary effects of other genes.

Cite this article

Yan Ning , Shuguang Duo , Xiwen Lin , Hongbo Zhang , Jifeng Fei , Bao Zhang , Yanyun Zeng , Dan Xie , Jian Chen , Xiaowei Liu , Chunsheng Han . Transcription factor PBX4 regulates limb development and haematopoiesis in mice[J]. Cell Proliferation, 2024 , 57(5) : e13580 . DOI: 10.1111/cpr.13580

References

Publishing order | Descend order by publishing year | Descend order by cited within
1
Selleri L, Zappavigna V, Ferretti E. ‘Building a perfect body’: control of vertebrate organogenesis by PBX-dependent regulatory networks. Genes Dev. 2019;33:258-275.

2
Galant R, Walsh CM, Carroll SB. Hox repression of a target gene: extradenticle-independent, additive action through multiple monomer binding sites. Development. 2002;129:3115-3126.

3
Laurent A, Bihan R, Omilli F, Deschamps S, Pellerin I. PBX proteins: much more than Hox cofactors. Int J Dev Biol. 2008;52:9-20.

4
Kamps MP, Murre C, Sun XH, Baltimore D. A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL. Cell. 1990;60:547-555.

5
Nourse J, Mellentin JD, Galili N, et al. Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell. 1990;60:535-545.

6
Monica K, Galili N, Nourse J, Saltman D, Cleary ML. PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1. Mol Cell Biol. 1991;11:6149-6157.

7
Wagner K, Mincheva A, Korn B, Lichter P, Popperl H. Pbx4, a new Pbx family member on mouse chromosome 8, is expressed during spermatogenesis. Mech Dev. 2001;103:127-131.

8
Rauskolb C, Smith KM, Peifer M, Wieschaus E. Extradenticle determines segmental identities throughout drosophila development. Development. 1995;121:3663-3673.

9
Rieckhof GE, Casares F, Ryoo HD, Abu-Shaar M, Mann RS. Nuclear translocation of extradenticle requires homothorax, which encodes an extradenticle-related homeodomain protein. Cell. 1997;91:171-183.

10
Selleri L, Depew MJ, Jacobs Y, et al. Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation. Development. 2001;128:3543-3557.

11
Selleri L, DiMartino J, van Deursen J, et al. The TALE homeodomain protein Pbx2 is not essential for development and long-term survival. Mol Cell Biol. 2004;24:5324-5331.

12
Capellini TD, Di Giacomo G, Salsi V, et al. Pbx1/Pbx2 requirement for distal limb patterning is mediated by the hierarchical control of Hox gene spatial distribution and shh expression. Development. 2006;133:2263-2273.

13
Rhee JW, Arata A, Selleri L, et al. Pbx3 deficiency results in central hypoventilation. Am J Pathol. 2004;165:1343-1350.

14
Gray PA, Fu H, Luo P, et al. Mouse brain organization revealed through direct genome-scale TF expression analysis. Science. 2004;306:2255-2257.

15
Popperl H, Rikhof H, Chang H, Haffter P, Kimmel CB, Moens CB. Lazarus is a novel pbx gene that globally mediates hox gene function in zebrafish. Mol. Cell. 2000;6:255-267.

16
He P, Williams BA, Trout D, et al. The changing mouse embryo transcriptome at whole tissue and single-cell resolution. Nature. 2020;583:760-767.

17
Kelly NH, Huynh NPT, Guilak F. Single cell RNA-sequencing reveals cellular heterogeneity and trajectories of lineage specification during murine embryonic limb development. Matrix Biol. 2020;89:1-10.

18
Fei L, Chen H, Ma L, et al. Systematic identification of cell-fate regulatory programs using a single-cell atlas of mouse development. Nat Genet. 2022;54:1051-1061.

19
Wegman-Ostrosky T, Savage SA. The genomics of inherited bone marrow failure: from mechanism to the clinic. Br J Haematol. 2017;177:526-542.

20
Tabula Muris Consortium, Overall coordination, Logistical coordination, et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris. Nature. 2018;562:367-372.

21
Berthelsen J, Zappavigna V, Mavilio F, Blasi F. Prep1, a novel functional partner of Pbx proteins. EMBO J. 1998;17:1423-1433.

22
Ferretti E, Villaescusa JC, Di Rosa P, et al. Hypomorphic mutation of the TALE gene Prep1 (pKnox1) causes a major reduction of Pbx and Meis proteins and a pleiotropic embryonic phenotype. Mol Cell Biol. 2006;26:5650-5662.

23
Schiaffino S, Dyar KA, Ciciliot S, Blaauw B, Sandri M. Mechanisms regulating skeletal muscle growth and atrophy. FEBS J. 2013;280:4294-4314.

24
Ulirsch JC, Verboon JM, Kazerounian S, et al. The genetic landscape of diamond-Blackfan anemia. Am J Hum Genet. 2018;103:930-947.

25
Capellini TD, Zappavigna V, Selleri L. Pbx homeodomain proteins: TALEnted regulators of limb patterning and outgrowth. Dev Dyn. 2011;240:1063-1086.

26
Barbosa-Morais NL, Irimia M, Pan Q, et al. The evolutionary landscape of alternative splicing in vertebrate species. Science. 2012;338:1587-1593.

27
Keren H, Lev-Maor G, Ast G. Alternative splicing and evolution: diversification, exon definition and function. Nat Rev Genet. 2010;11:345-355.

28
Soumillon M, Necsulea A, Weier M, et al. Cellular source and mechanisms of high transcriptome complexity in the mammalian testis. Cell Rep. 2013;3:2179-2190.

29
DiMartino JF, Selleri L, Traver D, et al. The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver. Blood. 2001;98:618-626.

30
Yang H, Wang H, Jaenisch R. Generating genetically modified mice using CRISPR/Cas-mediated genome engineering. Nat Protoc. 2014;9:1956-1968.

31
Ma L, Xie D, Luo M, et al. Identification and characterization of BEND2 as a key regulator of meiosis during mouse spermatogenesis. Sci Adv. 2022;8:eabn1606.

32
Kojima ML, de Rooij DG, Page DC. Amplification of a broad transcriptional program by a common factor triggers the meiotic cell cycle in mice. Elife. 2019;8:e43738.

33
Chen J, Gao C, Luo M, et al. MicroRNA-202 safeguards meiotic progression by preventing premature SEPARASE-mediated REC8 cleavage. EMBO Rep. 2022;23:e54298.

34
Ovchinnikov D. Alcian blue/alizarin red staining of cartilage and bone in mouse. Cold Spring Harb Protoc. 2009;2009:pdb.prot5170.

35
Marin-Llera JC, Chimal-Monroy J. A small population of resident limb bud mesenchymal cells express few MSC-associated markers, but the expression of these markers is increased immediately after cell culture. Cell Biol Int. 2018;42:570-579.

36
Zheng C, Ouyang YC, Jiang B, et al. Non-canonical RNA polyadenylation polymerase FAM46C is essential for fastening sperm head and flagellum in micedagger. Biol Reprod. 2019;100:1673-1685.

37
Epperlein H, Meulemans D, Bronner-Fraser M, Steinbeisser H, Selleck MA. Analysis of cranial neural crest migratory pathways in axolotl using cell markers and transplantation. Development. 2000;127:2751-2761.

Options
Outlines

/

〈 〉