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Members of the Sp family of transcription factors regulate gene expression via binding GC boxes within promoter regions. Unlike Sp1, which stimulates transcription, the closely related Sp3 can either repress or activate gene expression and is required for perinatal survival in mice. Here, we use RNA-seq and cellular phenotyping to show how Sp3 regulates murine fetal cell differentiation and proliferation. Homozygous Sp3-/- mice were smaller than wild-type and Sp+/- littermates, died soon after birth and had abnormal lung morphogenesis. RNA-seq of Sp3-/- fetal lung mesenchymal cells identified alterations in extracellular matrix production, developmental signaling pathways and myofibroblast/lipofibroblast differentiation. The lungs of Sp3-/- mice contained multiple structural defects, with abnormal endothelial cell morphology, lack of elastic fiber formation, and accumulation of lipid droplets within mesenchymal lipofibroblasts. Sp3-/- cells and mice also displayed cell cycle arrest, with accumulation in G0/G1 and reduced expression of numerous cell cycle regulators including Ccne1. These data detail the global impact of Sp3 on in vivo mouse gene expression and development.

Competing Interests: Competing interests The authors declare no competing or financial interests.

Titel:	Sp3 is essential for normal lung morphogenesis and cell cycle progression during mouse embryonic development.
Autor/in / Beteiligte Person:	McCoy, AM ; Lakhdari, O ; Shome, S ; Caoili, K ; Hernandez, GE ; Aghaeepour, N ; Butcher, LD ; Fisch, K ; Prince, LS
Zeitschrift:	Development (Cambridge, England), Jg. 150 (2023-03-01), Heft 5
Veröffentlichung:	Cambridge Eng : Company Of Biologists Limited ; <i>Original Publication</i>: [Cambridge] : Company of Biologists, [c1987-, 2023
Medientyp:	academicJournal
ISSN:	1477-9129 (electronic)
DOI:	10.1242/dev.200839
Schlagwort:	Animals Mice Cell Division Lung Promoter Regions, Genetic Sp1 Transcription Factor genetics Sp1 Transcription Factor metabolism Embryonic Development Transcription Factors metabolism
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural Language: English [Development] 2023 Mar 01; Vol. 150 (5). <i>Date of Electronic Publication: </i>2023 Mar 03. MeSH Terms: Embryonic Development* ; Transcription Factors* / metabolism ; Animals ; Mice ; Cell Division ; Lung ; Promoter Regions, Genetic ; Sp1 Transcription Factor / genetics ; Sp1 Transcription Factor / metabolism References: Pharmacol Ther. 2015 Aug;152:111-24. (PMID: 25960131) ; Sci Rep. 2020 Mar 20;10(1):5118. (PMID: 32198404) ; Sci Rep. 2018 Jan 18;8(1):1138. (PMID: 29348684) ; Biochim Biophys Acta Gene Regul Mech. 2017 May;1860(5):590-597. (PMID: 27697431) ; Matrix Biol. 2018 Nov;73:77-104. (PMID: 29524630) ; Bioinformatics. 2010 Jan 1;26(1):139-40. (PMID: 19910308) ; Science. 1985 Nov 1;230(4725):511-7. (PMID: 2996137) ; Sci Rep. 2019 Oct 23;9(1):15202. (PMID: 31645574) ; Cell Rep. 2017 Aug 8;20(6):1319-1334. (PMID: 28793257) ; Dev Dyn. 2005 Jun;233(2):553-61. (PMID: 15830384) ; Cell. 1983 Mar;32(3):669-80. (PMID: 6187469) ; EMBO J. 1994 Aug 15;13(16):3843-51. (PMID: 8070411) ; Genome Biol. 2003;4(2):206. (PMID: 12620113) ; Nucleic Acids Res. 1999 Aug 1;27(15):2991-3000. (PMID: 10454592) ; J Appl Physiol (1985). 2020 May 1;128(5):1287-1298. (PMID: 32078464) ; Nucleic Acids Res. 2019 Jul 2;47(W1):W199-W205. (PMID: 31114916) ; J Clin Invest. 2020 Jun 1;130(6):2859-2871. (PMID: 32338642) ; Trends Cell Biol. 2019 Sep;29(9):752-763. (PMID: 31300188) ; J Virol. 1996 Jan;70(1):188-98. (PMID: 8523525) ; Mol Cell. 2002 Oct;10(4):831-42. (PMID: 12419227) ; Stem Cells. 2021 Oct;39(10):1382-1394. (PMID: 34048616) ; Front Cell Dev Biol. 2021 May 26;9:645400. (PMID: 34124037) ; Nature. 1995 Aug 17;376(6541):609-12. (PMID: 7637813) ; Epigenetics Chromatin. 2019 Jun 4;12(1):33. (PMID: 31164147) ; Nucleic Acids Res. 2015 Apr 20;43(7):e47. (PMID: 25605792) ; J Biol Chem. 2013 May 24;288(21):15318-25. (PMID: 23558680) ; Cell Cycle. 2013 Jun 15;12(12):1828-34. (PMID: 23676218) ; EMBO J. 1996 Oct 15;15(20):5659-67. (PMID: 8896459) ; Genomics. 2005 May;85(5):551-6. (PMID: 15820306) ; Yale J Biol Med. 2016 Dec 23;89(4):513-525. (PMID: 28018142) ; J Immunol. 2022 Apr 15;208(8):1947-1959. (PMID: 35354612) ; Genome Biol. 2010;11(3):R25. (PMID: 20196867) ; Dev Cell. 2011 Aug 16;21(2):193-215. (PMID: 21839917) ; Genome Res. 2003 Nov;13(11):2498-504. (PMID: 14597658) ; Gene. 1999 Oct 1;238(2):291-300. (PMID: 10570957) ; Am J Respir Cell Mol Biol. 2016 Apr;54(4):532-45. (PMID: 26414960) ; Science. 2017 Jun 23;356(6344):. (PMID: 28546318) ; Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517) ; EMBO J. 2000 Feb 15;19(4):655-61. (PMID: 10675334) ; Genome Biol. 2014 Feb 03;15(2):R29. (PMID: 24485249) ; Mol Biol Cell. 2005 Sep;16(9):4073-83. (PMID: 15987735) ; Genes Dev. 1991 Sep;5(9):1646-56. (PMID: 1885006) ; Matrix Biol. 2018 Nov;73:6-20. (PMID: 29331337) ; Compr Physiol. 2021 Jun 30;11(3):2227-2247. (PMID: 34190345) ; Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613. (PMID: 30476243) ; Dev Biol. 2017 May 15;425(2):161-175. (PMID: 28408205) ; Proc Natl Acad Sci U S A. 1995 Apr 25;92(9):3953-7. (PMID: 7732011) ; J Am Heart Assoc. 2020 Jan 7;9(1):e014103. (PMID: 31880978) ; Mol Cell Biol. 1992 Oct;12(10):4251-61. (PMID: 1341900) ; Matrix Biol. 2018 Oct;71-72:112-127. (PMID: 29625182) ; Bioinformatics. 2013 Jan 1;29(1):15-21. (PMID: 23104886) ; J Immunol. 2016 Apr 15;196(8):3411-20. (PMID: 26951798) ; EMBO J. 2002 Oct 1;21(19):5206-15. (PMID: 12356736) ; Cell. 2004 Feb 20;116(4):499-509. (PMID: 14980218) ; Biochemistry. 1995 Dec 19;34(50):16503-8. (PMID: 8845379) ; Nature. 2003 Jun 19;423(6942):876-81. (PMID: 12815434) ; Cell. 1997 May 16;89(4):619-28. (PMID: 9160753) ; PLoS Genet. 2010 Nov 11;6(11):e1001203. (PMID: 21085687) ; Mech Dev. 2001 Aug;106(1-2):77-83. (PMID: 11472836) ; Cell Syst. 2015 Oct 28;1(4):302-305. (PMID: 26594663) ; J Clin Invest. 2013 Jul;123(7):3025-36. (PMID: 23921127) ; Blood. 2003 Aug 1;102(3):858-66. (PMID: 12676787) ; Development. 2014 Dec;141(24):4751-62. (PMID: 25395457) ; J Biol Chem. 1997 Feb 14;272(7):4021-6. (PMID: 9020109) ; Immunol Lett. 2002 Jun 3;82(1-2):85-91. (PMID: 12008039) ; Dev Biol. 1994 Feb;161(2):615-25. (PMID: 7508872) ; Biochem Cell Biol. 2004 Aug;82(4):460-71. (PMID: 15284899) Grant Information: R01 HL086324 United States HL NHLBI NIH HHS; R01 HL126703 United States HL NHLBI NIH HHS; UL1 TR001442 United States TR NCATS NIH HHS Contributed Indexing: Keywords: Alveolar development; Cell proliferation; Lipofibroblast; Lung mesenchyme; Myofibroblast; Transcriptional regulation Substance Nomenclature: 0 (Sp1 Transcription Factor) ; 0 (Transcription Factors) Entry Date(s): Date Created: 20230210 Date Completed: 20230310 Latest Revision: 20230916 Update Code: 20231215 PubMed Central ID: PMC10110423

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Sp3 is essential for normal lung morphogenesis and cell cycle progression during mouse embryonic development.