miRNA regulation of Sdf1 chemokine signaling provides genetic robustness to germ cell migration.
microRNAs (miRNAs) function as genetic rheostats to control gene output. Based on their role as modulators, it has been postulated that miRNAs canalize development and provide genetic robustness. Here, we uncover a previously unidentified regulatory layer of chemokine signaling by miRNAs that confers genetic robustness on primordial germ cell (PGC) migration. In zebrafish, PGCs are guided to the gonad by the ligand Sdf1a, which is regulated by the sequestration receptor Cxcr7b. We find that miR-430 regulates sdf1a and cxcr7 mRNAs. Using target protectors, we demonstrate that miR-430-mediated regulation of endogenous sdf1a (also known as cxcl12a) and cxcr7b (i) facilitates dynamic expression of sdf1a by clearing its mRNA from previous expression domains, (ii) modulates the levels of the decoy receptor Cxcr7b to avoid excessive depletion of Sdf1a and (iii) buffers against variation in gene dosage of chemokine signaling components to ensure accurate PGC migration. Our results indicate that losing miRNA-mediated regulation can expose otherwise buffered genetic lesions leading to developmental defects.
Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA.
Alison A
AA
Staton
Holger
H
Knaut
Antonio J
AJ
Giraldez
D000818:Animals; D002465:Cell Movement / Q000235:genetics*; D054377:Chemokine CXCL12 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D005854:Germ Cells / Q000502:physiology*; D035683:MicroRNAs / Q000502:physiology; D008954:Models, Biological; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
C519524:CXCR7 protein, zebrafish; D054377:Chemokine CXCL12; D035683:MicroRNAs; C557527:Mirn430 microRNA, zebrafish; D054387:Receptors, CXCR; D029961:Zebrafish Proteins
Nat Rev Genet. 2003 Sep;4(9):690-700
12951570
Nat Rev Genet. 2007 Jun;8(6):450-61
17510665
J Immunol. 2003 Jan 1;170(1):421-9
12496427
Dev Cell. 2009 Apr;16(4):517-27
19386261
Genes Dev. 2007 Sep 15;21(18):2277-82
17761811
Cancer Lett. 2008 Aug 28;267(2):226-44
18579287
Genes Dev. 2010 Jul 1;24(13):1339-44
20595229
Cell. 2008 Feb 8;132(3):463-73
18267076
Cell. 2009 Apr 17;137(2):273-82
19379693
Science. 2007 Oct 12;318(5848):271-4
17761850
Nature. 2003 Jan 16;421(6920):279-82
12508118
Cell. 2002 Nov 27;111(5):647-59
12464177
Nat Rev Genet. 2004 May;5(5):396-400
15143321
Genome Res. 2009 Jan;19(1):92-105
18955434
Genes Dev. 2009 Oct 1;23(19):2272-7
19797767
Trends Immunol. 2007 Jul;28(7):299-307
17560169
EMBO Rep. 2010 Aug;11(8):590-7
20651740
Neuron. 2005 Sep 1;47(5):653-66
16129396
Annu Rev Genomics Hum Genet. 2009;10:451-81
19715442
J Mol Biol. 2005 Jun 10;349(3):501-14
15890368
Nature. 1998 Nov 26;396(6709):336-42
9845070
Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12023-8
16099838
Annu Rev Biophys Biomol Struct. 2007;36:413-34
17477840
Development. 2008 Aug;135(15):2521-9
18579679
Nat Genet. 2006 Jun;38 Suppl:S20-4
16736020
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16297-302
12444253
Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):11980-5
14530388
Genes Dev. 2009 Mar 1;23(5):619-32
19240126
Nat Rev Genet. 2004 Nov;5(11):826-37
15520792
PLoS Biol. 2010 Jun 15;8(6):e1000396
20563308
N Engl J Med. 1998 Feb 12;338(7):436-45
9459648
PLoS One. 2010 Feb 11;5(2):e9175
20161793
Science. 2008 Oct 3;322(5898):89-92
18719251
Genes Dev. 2006 Oct 15;20(20):2793-805
17015424
Cell. 2009 Jan 23;136(2):215-33
19167326
Development. 2002 Jan;129(1):25-36
11782398
Cell. 2008 Oct 17;135(2):216-26
18957198
Science. 2006 Apr 7;312(5770):75-9
16484454
Development. 2009 Apr;136(8):1223-9
19304885
Genome Res. 2009 May;19(5):734-43
19411598
Science. 2005 May 6;308(5723):833-8
15774722
Cell. 2005 Dec 16;123(6):1133-46
16337999
Nat Genet. 2003 Nov;35(3):217-8
14528306
J Exp Med. 1997 Jan 6;185(1):111-20
8996247
Nature. 2001 Mar 1;410(6824):50-6
11242036
Science. 2005 Sep 23;309(5743):2010-3
16179466
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2963-8
18287065