title: Time-dependent gene expression analysis of the developing superior olivary complex.
abstract: The superior olivary complex (SOC) is an essential auditory brainstem relay involved in sound localization. To identify the genetic program underlying its maturation, we profiled the rat SOC transcriptome at postnatal days 0, 4, 16, and 25 (P0, P4, P16, and P25, respectively), using genome-wide microarrays (41,012 oligonucleotides (oligos)). Differences in gene expression between two consecutive stages were highest between P4 and P16 (3.6%) and dropped to 0.06% between P16 and P25. To identify SOC-related genetic programs, we also profiled the entire brain at P4 and P25. The number of differentially expressed oligonucleotides between SOC and brain almost doubled from P4 to P25 (4.4% versus 7.6%). These data demonstrate considerable molecular specification around hearing onset, which is rapidly finalized. Prior to hearing onset, several transcription factors associated with the peripheral auditory system were up-regulated, probably coordinating the development of the auditory system. Additionally, crystallin-γ subunits and serotonin-related genes were highly expressed. The molecular repertoire of mature neurons was sculpted by SOC-related up- and down-regulation of voltage-gated channels and G-proteins. Comparison with the brain revealed a significant enrichment of hearing impairment-related oligos in the SOC (26 in the SOC, only 11 in the brain). Furthermore, 29 of 453 SOC-related oligos mapped within 19 genetic intervals associated with hearing impairment. Together, we identified sequential genetic programs in the SOC, thereby pinpointing candidates that may guide its development and ensure proper function. The enrichment of hearing impairment-related genes in the SOC may have implications for restoring hearing because central auditory structures might be more severely affected than previously appreciated.
authors.affiliation: From the Animal Physiology Group, Department of Biology, University of Kaiserslautern, D-67663 Kaiserslautern, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Ehmann
authors.affiliation: the Neurogenetics Group, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany.
authors.forename: Heiner
authors.initials: H
authors.lastname: Hartwich
authors.affiliation: the Department of System Analysis, Prognosis, and Control, Fraunhofer Institute for Industrial Mathematics (ITWM), D-67663 Kaiserslautern, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Salzig
authors.affiliation: From the Animal Physiology Group, Department of Biology, University of Kaiserslautern, D-67663 Kaiserslautern, Germany.
authors.forename: Nadja
authors.initials: N
authors.lastname: Hartmann
authors.affiliation: Biotechnologisches Zentrum, TU Dresden, D-01062 Dresden, Germany.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Clément-Ziza
authors.affiliation: the Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Kathy
authors.initials: K
authors.lastname: Ushakov
authors.affiliation: the Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Karen B
authors.initials: KB
authors.lastname: Avraham
authors.affiliation: the Department of Systematics and Evolutionary Biology and.
authors.forename: Olaf R P
authors.initials: ORP
authors.lastname: Bininda-Emonds
authors.affiliation: the Computational Theoretical Physics Group, University of Oldenburg, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany, and.
authors.forename: Alexander K
authors.initials: AK
authors.lastname: Hartmann
authors.affiliation: the Department of System Analysis, Prognosis, and Control, Fraunhofer Institute for Industrial Mathematics (ITWM), D-67663 Kaiserslautern, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Lang
authors.affiliation: From the Animal Physiology Group, Department of Biology, University of Kaiserslautern, D-67663 Kaiserslautern, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Friauf
authors.affiliation: the Neurogenetics Group, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany,; the Center for Neuroscience, Carl von Ossietzky University Oldenburg, 26111 Oldenburg, Germany,; the Center of Excellence Hearing4all, 26111 Oldenburg, Germany. Electronic address: hans.g.nothwang@uni-oldenburg.de.
authors.forename: Hans Gerd
authors.initials: HG
authors.lastname: Nothwang
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006309:Hearing / Q000502:physiology*; D006801:Humans; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D059467:Transcriptome / Q000502:physiology*
chemical_list: D009419:Nerve Tissue Proteins
keywords: Auditory Processing Disorder; Circuit Development; Deafness; Genetic Diseases; Neurodevelopment; Neurodifferentiation; Neuroprotection; Retrocochlear Function; Transcription Factors
references.citation: J Comp Neurol. 1995 Feb 20;352(4):607-25
references.pmid: 7722003
references.citation: Nat Protoc. 2009;4(1):44-57
references.pmid: 19131956
references.citation: Anal Biochem. 2002 Aug 15;307(2):304-15
references.pmid: 12202248
references.citation: Genomics. 1999 Mar 15;56(3):340-3
references.pmid: 10087202
references.citation: Neurosci Lett. 1990 Nov 27;120(1):58-61
references.pmid: 1705672
references.citation: Annu Rev Physiol. 1999;61:477-96
references.pmid: 10099698
references.citation: J Comp Neurol. 1998 Jan 5;390(1):20-40
references.pmid: 9456173
references.citation: Mol Cell Proteomics. 2007 May;6(5):895-907
references.pmid: 17264069
references.citation: J Comp Neurol. 2007 Oct 10;504(5):533-49
references.pmid: 17701984
references.citation: J Neurophysiol. 2006 Sep;96(3):1547-55
references.pmid: 16775198
references.citation: PLoS Genet. 2013;9(2):e1003249
references.pmid: 23408898
references.citation: Ear Hear. 2003 Jun;24(3):206-14
references.pmid: 12799542
references.citation: Neuron. 2012 Oct 4;76(1):175-91
references.pmid: 23040814
references.citation: Nat Neurosci. 2009 Aug;12(8):996-1002
references.pmid: 19633666
references.citation: Curr Opin Neurol. 2002 Feb;15(1):31-3
references.pmid: 11796948
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16406-7
references.pmid: 22996329
references.citation: J Neurosci. 2009 Sep 9;29(36):11123-33
references.pmid: 19741118
references.citation: PLoS One. 2012;7(11):e49503
references.pmid: 23152916
references.citation: Development. 1997 Oct;124(19):3693-702
references.pmid: 9367425
references.citation: Physiol Rev. 2001 Apr;81(2):871-927
references.pmid: 11274346
references.citation: Brain Res. 2011 Jan 7;1367:360-71
references.pmid: 20946889
references.citation: Neurosci Res. 2008 Aug;61(4):420-8
references.pmid: 18554735
references.citation: Mol Cell Neurosci. 2001 Dec;18(6):632-48
references.pmid: 11749039
references.citation: J Neurosci. 2012 Oct 17;32(42):14602-16
references.pmid: 23077046
references.citation: J Neurosci. 2006 Jan 4;26(1):345-53
references.pmid: 16399705
references.citation: Nat Genet. 2002 Aug;31(4):363-9
references.pmid: 12091910
references.citation: Am J Hum Genet. 2008 Apr;82(4):982-91
references.pmid: 18394579
references.citation: Can J Neurol Sci. 1982 Nov;9(4):429-33
references.pmid: 7151027
references.citation: J Comp Neurol. 2005 Dec 19;493(3):460-74
references.pmid: 16261529
references.citation: Science. 1999 Jun 11;284(5421):1837-41
references.pmid: 10364557
references.citation: J Comp Neurol. 1993 Feb 8;328(2):161-84
references.pmid: 8423239
references.citation: Cell. 1993 Jul 30;74(2):395-404
references.pmid: 8343963
references.citation: J Neurophysiol. 2005 Feb;93(2):819-28
references.pmid: 15456797
references.citation: J Physiol. 2009 Jun 1;587(Pt 11):2417-8
references.pmid: 19483247
references.citation: Nature. 2000 Jul 27;406(6794):419-22
references.pmid: 10935639
references.citation: Genome Res. 2009 Feb;19(2):327-35
references.pmid: 19029536
references.citation: Nat Rev Neurosci. 2003 Dec;4(12):1002-12
references.pmid: 14618156
references.citation: J Physiol. 2007 Sep 1;583(Pt 2):647-61
references.pmid: 17627992
references.citation: J Neurosci. 2006 Oct 11;26(41):10407-19
references.pmid: 17035525
references.citation: Nature. 2008 Dec 11;456(7223):795-9
references.pmid: 18978774
references.citation: Neuron. 2010 Oct 21;68(2):293-308
references.pmid: 20955936
references.citation: J Neurosci. 2003 May 15;23(10):4134-45
references.pmid: 12764101
references.citation: J Comp Neurol. 1993 Aug 1;334(1):59-74
references.pmid: 8408759
references.citation: Neuron. 2008 Jul 10;59(1):125-37
references.pmid: 18614034
references.citation: J Comp Neurol. 2001 Jan 22;429(4):615-30
references.pmid: 11135239
references.citation: Dev Med Child Neurol. 2012 Jan;54(1):23-9
references.pmid: 22142282
references.citation: Cell Tissue Res. 2005 Apr;320(1):33-50
references.pmid: 15714284
references.citation: Dev Biol. 2008 Oct 1;322(1):167-78
references.pmid: 18703040
references.citation: J Biol Chem. 2006 Jun 2;281(22):15582-91
references.pmid: 16595659
references.citation: Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9529-34
references.pmid: 23690594
references.citation: Nat Neurosci. 2009 Jun;12(6):711-7
references.pmid: 19471270
references.citation: Cell. 2010 Mar 5;140(5):744-52
references.pmid: 20211142
references.citation: Science. 2004 Dec 24;306(5705):2255-7
references.pmid: 15618518
references.citation: Nat Neurosci. 2010 Feb;13(2):232-8
references.pmid: 20081852
references.citation: J Neurochem. 1999 Feb;72(2):669-75
references.pmid: 9930739
references.citation: Adv Exp Med Biol. 2012;739:173-86
references.pmid: 22399402
references.citation: Nat Genet. 2001 Feb;27(2):143-9
references.pmid: 11175778
references.citation: Nat Neurosci. 2009 Jun;12(6):703-10
references.pmid: 19471269
references.citation: Hear Res. 2008 Nov;245(1-2):65-72
references.pmid: 18793710
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Science. 2009 Jun 26;324(5935):1720-3
references.pmid: 19443739
references.citation: Ear Hear. 2010 Jun;31(3):325-35
references.pmid: 20090530
references.citation: Brain Res. 1987 Mar;429(1):75-84
references.pmid: 3567661
references.citation: J Physiol. 2010 Sep 1;588(Pt 17):3187-200
references.pmid: 20519310
references.citation: Hum Mol Genet. 2012 Sep 1;21(17):3896-909
references.pmid: 22678062
references.citation: J Neurobiol. 1999 Dec;41(4):596-611
references.pmid: 10590182
references.citation: J Neurosci. 2012 Feb 15;32(7):2538-43
references.pmid: 22396426
references.citation: J Neurobiol. 1991 Nov;22(8):837-54
references.pmid: 1663990
references.citation: J Neurosci. 2011 Jun 1;31(22):8280-94
references.pmid: 21632949
references.citation: J Neurosci Methods. 1992 Feb;41(2):153-66
references.pmid: 1564950
references.citation: Dev Cell. 2007 Sep;13(3):325-37
references.pmid: 17765677
references.citation: J Comp Neurol. 1999 Sep 13;412(1):17-37
references.pmid: 10440707
references.citation: Bioinformatics. 2005 Aug 15;21(16):3439-40
references.pmid: 16082012
references.citation: Mol Cell Neurosci. 2008 Mar;37(3):471-9
references.pmid: 18178099
references.citation: Nat Genet. 1998 Feb;18(2):171-3
references.pmid: 9462749
references.citation: Brain Res. 2011 Jun 29;1398:102-12
references.pmid: 21636076