Overlapping and distinct pRb pathways in the mammalian auditory and vestibular organs.
Retinoblastoma gene (Rb1) is required for proper cell cycle exit in the developing mouse inner ear and its deletion in the embryo leads to proliferation of sensory progenitor cells that differentiate into hair cells and supporting cells. In a conditional hair cell Rb1 knockout mouse, Pou4f3-Cre-pRb(-/-), pRb(-/-) utricular hair cells differentiate and survive into adulthood whereas differentiation and survival of pRb(-/-) cochlear hair cells are impaired. To comprehensively survey the pRb pathway in the mammalian inner ear, we performed microarray analysis of (pRb(-/-) cochlea and utricle. The comparative analysis shows that the core pathway shared between pRb(-/-) cochlea and utricle is centered on E2F, the key pathway that mediates pRb function. A majority of differentially expressed genes and enriched pathways are not shared but uniquely associated with pRb(-/-) cochlea or utricle. In pRb(-/-) cochlea, pathways involved in early inner ear development such as Wnt/β-catenin and Notch were enriched, whereas pathways involving in proliferation and survival are enriched in pRb(-/-) utricle. Clustering analysis showed that the pRb(-/-) inner ear has characteristics of a younger control inner ear, an indication of delayed differentiation. We created a transgenic mouse model (ER-Cre-pRb(flox/flox)) in which Rb1 can be acutely deleted postnatally. Acute Rb1 deletion in the adult mouse fails to induce proliferation or cell death in inner ear, strongly indicating that Rb1 loss in these postmitotic tissues can be effectively compensated for, or that pRb-mediated changes in the postmitotic compartment result in events that are functionally irreversible once enacted. This study thus supports the concept that pRb-regulated pathways relevant to hair cell development, encompassing proliferation, differentiation and survival, act predominantly during early development.
Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts, USA.
Mingqian
M
Huang
Cyrille
C
Sage
Yong
Y
Tang
Sang Goo
SG
Lee
Marco
M
Petrillo
Philip W
PW
Hinds
Zheng-Yi
ZY
Chen
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D016000:Cluster Analysis; D003051:Cochlea / Q000378:metabolism; D053263:Gene Regulatory Networks; D006198:Hair Cells, Auditory / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*; D012444:Saccule and Utricle / Q000378:metabolism; D015398:Signal Transduction; D014722:Vestibule, Labyrinth / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D051880:Receptors, Notch; D016160:Retinoblastoma Protein; D051153:Wnt Proteins; D051176:beta Catenin
Nat Protoc. 2009;4(1):44-57
19131956
Development. 2005 May;132(10):2377-88
15843406
Gene Expr Patterns. 2003 Aug;3(4):389-95
12915300
Nat Rev Mol Cell Biol. 2008 Sep;9(9):713-24
18719710
Cell Cycle. 2008 Aug 15;7(16):2544-52
18719374
Naturwissenschaften. 1988 Jun;75(6):319-20
3205314
J Biol Chem. 2008 Apr 4;283(14):9071-9
18245774
J Comp Neurol. 2004 Sep 27;477(4):412-21
15329890
Int J Dev Biol. 2007;51(6-7):585-95
17891719
Antioxid Redox Signal. 2009 May;11(5):1165-90
19014342
Mol Vis. 2010 Jul 13;16:1292-303
20664703
Mol Biol Cell. 2005 Nov;16(11):5455-63
16176979
Development. 1993 Dec;119(4):1041-53
8306874
Science. 1988 Jun 24;240(4860):1772-4
3381100
EMBO J. 1996 Feb 1;15(3):457-67
8599929
Trends Biochem Sci. 2004 Aug;29(8):409-17
15362224
Nat Cell Biol. 2007 Aug;9(8):883-92
17618275
Dev Dyn. 2008 Nov;237(11):3305-12
18942141
Nat Cell Biol. 2003 May;5(5):422-6
12717441
Development. 2002 May;129(10):2495-505
11973280
Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4084-8
10097167
Dev Biol. 2002 Apr 15;244(2):305-18
11944939
Eur J Cell Biol. 1996 Apr;69(4):327-34
8741214
J Cell Sci. 2004 May 1;117(Pt 11):2173-81
15126619
Genome Biol. 2003;4(5):P3
12734009
Mol Cell Biol. 2010 Apr;30(7):1729-45
20100864
Development. 1999 Apr;126(8):1581-90
10079221
Hear Res. 1993 Dec;71(1-2):125-36
8113131
Science. 1988 Jun 24;240(4860):1774-6
3381101
Nat Genet. 2008 Apr;40(4):411-20
18311137
J Biol Chem. 2010 Jan 1;285(1):392-400
19864427
Proc Natl Acad Sci U S A. 2008 Jan 15;105(2):781-5
18178626
Nature. 2008 Sep 25;455(7212):552-6
18794899
J Assoc Res Otolaryngol. 2002 Jun;3(2):140-8
12162364
Dev Biol. 2003 Sep 1;261(1):149-64
12941626
J Neurosci. 2010 Apr 28;30(17):5927-36
20427652
J Neurosci. 2007 Feb 7;27(6):1434-44
17287518
Proc Natl Acad Sci U S A. 2006 May 9;103(19):7345-50
16648263
Cancer Cell. 2010 Apr 13;17(4):376-87
20385362
J Cell Biol. 2008 Oct 6;183(1):129-41
18838555
Nature. 2006 Jan 26;439(7075):430-6
16437107
EMBO J. 2007 Apr 18;26(8):2083-93
17380128
J Biol Chem. 1999 Sep 24;274(39):27632-41
10488103
Cell Mol Life Sci. 2006 Apr;63(7-8):767-80
16465443
Cancer Res. 2005 Dec 15;65(24):11762-70
16357189
Science. 2005 Feb 18;307(5712):1114-8
15653467
Science. 1993 Mar 12;259(5101):1616-9
8456284
J Biol Chem. 2002 Jun 14;277(24):21458-67
11940566
Cell Cycle. 2004 Mar;3(3):372-9
14726697
Oncogene. 2004 Aug 19;23(37):6250-60
15195143
Dev Biol. 1999 Sep 1;213(1):180-93
10452855
Science. 1993 Mar 12;259(5101):1619-22
8456285
Nat Rev Neurosci. 2006 Nov;7(11):837-49
17053809
Cell Cycle. 2006 Nov;5(22):2609-12
17106260