title: Sexually dimorphic fin regeneration in zebrafish controlled by androgen/GSK3 signaling.
abstract: Certain fish and amphibians regenerate entire fins and limbs after amputation, whereas such potential is absent in birds and limited in mammals to digit tips [1, 2]. Additionally, regenerative success can change during life stages. Anuran tadpoles gradually lose the capacity to regenerate limbs [3, 4], and digit regeneration occurs more effectively in fetal mice and human children than adults [5-8]. Little is known about mechanisms that control regenerative capacity. Here, we identify an unexpected difference between male and female zebrafish in the regenerative potential of a major appendage. Males display regenerative defects in amputated pectoral fins, caused by impaired blastemal proliferation. This regenerative failure emerges after sexual maturity, is mimicked in androgen-treated females, and is suppressed in males by androgen receptor antagonism. Androgen signaling maintains expression of dkk1b and igfbp2a, which encode secreted inhibitors of Wnt and Igf signaling, respectively. Furthermore, the regulatory target of Wnts and Igfs, GSK3β, is inefficiently inactivated in male fin regenerates compared with females. Pharmacological inhibition of GSK3 in males increases blastemal proliferation and restores regenerative pattern. Our findings identify a natural sex bias in appendage regenerative capacity and indicate an underlying regulatory circuit in which androgen locally restricts key morphogenetic programs after amputation.
authors.affiliation: Department of Cell Biology and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Nachtrab
authors.forename: Michael
authors.initials: M
authors.lastname: Czerwinski
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Poss
mesh_terms: D000728:Androgens / Q000378:metabolism*; D058500:Animal Fins / Q000502:physiology*; D000818:Animals; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D012727:Sex Characteristics; D012741:Sexual Maturation; D015398:Signal Transduction; D015027:Zebrafish / Q000235:genetics / Q000502:physiology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000728:Androgens; D018971:Insulin-Like Growth Factor Binding Protein 2; D036341:Intercellular Signaling Peptides and Proteins; D011944:Receptors, Androgen; D029961:Zebrafish Proteins; C501128:dkk1b protein, zebrafish; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
references.citation: Nature. 2009 Jul 2;460(7251):60-5
references.pmid: 19571878
references.citation: J Cell Physiol. 2010 Aug;224(2):305-10
references.pmid: 20432458
references.citation: Annu Rev Cell Dev Biol. 2008;24:525-49
references.pmid: 18598212
references.citation: Aquat Toxicol. 2011 Jan 25;101(2):447-58
references.pmid: 21126777
references.citation: Science. 2007 Aug 10;317(5839):807-10
references.pmid: 17690295
references.citation: Chem Biol. 2003 Dec;10(12):1255-66
references.pmid: 14700633
references.citation: J Steroid Biochem Mol Biol. 1997 Jan;60(1-2):121-9
references.pmid: 9182866
references.citation: Nature. 2005 Feb 17;433(7027):760-4
references.pmid: 15716955
references.citation: J Clin Invest. 2002 Sep;110(5):615-24
references.pmid: 12208862
references.citation: Development. 1994 Jul;120(7):1861-72
references.pmid: 7924993
references.citation: Nat Rev Mol Cell Biol. 2001 Oct;2(10):769-76
references.pmid: 11584304
references.citation: Nature. 1968 Oct 5;220(5162):83-5
references.pmid: 5677454
references.citation: J Dermatol Sci. 2011 Jan;61(1):1-6
references.pmid: 21167691
references.citation: Dev Cell. 2011 May 17;20(5):713-24
references.pmid: 21571227
references.citation: Development. 1995 Apr;121(4):1065-76
references.pmid: 7538067
references.citation: Aust Paediatr J. 1972 Apr;8(2):86-9
references.pmid: 5074173
references.citation: Dev Cell. 2009 Jul;17(1):9-26
references.pmid: 19619488
references.citation: Nat Rev Genet. 2010 Oct;11(10):710-22
references.pmid: 20838411
references.citation: Cell. 2010 Dec 23;143(7):1136-48
references.pmid: 21183076
references.citation: Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 1994 Nov;109(3):i-v
references.pmid: 7894885
references.citation: Science. 2011 Feb 25;331(6020):1078-80
references.pmid: 21350179
references.citation: Science. 2005 Dec 23;310(5756):1957-60
references.pmid: 16373575
references.citation: Development. 2005 Dec;132(23):5173-83
references.pmid: 16251209
references.citation: Development. 2007 Feb;134(3):479-89
references.pmid: 17185322
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 31;106(13):5165-70
references.pmid: 19289839
references.citation: Science. 1982 Aug 20;217(4561):747-50
references.pmid: 7100922
references.citation: Nature. 2006 Sep 28;443(7110):421-6
references.pmid: 16957735
references.citation: Toxicol Sci. 2001 Mar;60(1):56-62
references.pmid: 11222873
references.citation: Development. 2008 Sep;135(18):3063-70
references.pmid: 18701543
references.citation: JAMA. 2004 Sep 22;292(12):1431-2
references.pmid: 15383512
references.citation: Ecotoxicology. 2009 Jan;18(1):122-33
references.pmid: 18807270
references.citation: Curr Biol. 2007 Aug 21;17(16):1390-5
references.pmid: 17683938
references.citation: Development. 2010 Mar;137(6):871-9
references.pmid: 20179093
references.citation: Annu Rev Cell Dev Biol. 2004;20:781-810
references.pmid: 15473860
references.citation: Oncogene. 2001 Jan 11;20(2):252-9
references.pmid: 11313952
references.citation: Nature. 2006 Sep 28;443(7110):453-7
references.pmid: 16957737
references.citation: Genes Dev. 2006 Dec 1;20(23):3232-7
references.pmid: 17114576
references.citation: Development. 1998 Nov;125(21):4175-84
references.pmid: 9753672
references.citation: J Pediatr Surg. 1974 Dec;9(6):853-58
references.pmid: 4473530
references.citation: Oncogene. 2006 Dec 4;25(57):7482-91
references.pmid: 17143292
references.citation: Gerontology. 2011;57(1):53-65
references.pmid: 20332600
references.citation: Nature. 1995 Dec 21-28;378(6559):785-9
references.pmid: 8524413
references.citation: J Morphol. 1962 Jan;110:61-77
references.pmid: 13885494
references.citation: J Exp Zool. 1986 Oct;240(1):47-54
references.pmid: 3772329