title: Prenatal expression of MET receptor tyrosine kinase in the fetal mouse dorsal raphe nuclei and the visceral motor/sensory brainstem.
abstract: Signaling via MET receptor tyrosine kinase (MET) has been implicated in a number of neurodevelopmental events, including cell migration, dendritic and axonal development and synaptogenesis. Related to its role in the development of forebrain circuitry, we recently identified a functional promoter variant of the MET gene that is associated with autism spectrum disorder (ASD). The association of the MET promoter variant rs1858830 C allele is significantly enriched in families with a child who has ASD and co-occurring gastrointestinal conditions. The expression of MET in the forebrain had been mapped in detail in the developing mouse and rhesus macaque. However, in mammals, its expression in the developing brainstem has not been studied extensively throughout developmental stages. Brainstem and autonomic circuitry are implicated in ASD pathophysiology and in gastrointestinal dysfunction. To advance our understanding of the neurodevelopmental influences of MET signaling in brainstem circuitry development, we employed in situ hybridization and immunohistochemistry to map the expression of Met and its ligand, Hgf, through prenatal development of the mouse midbrain and hindbrain. Our results reveal a highly selective expression pattern of Met in the brainstem, including a subpopulation of neurons in cranial motor nuclei (nVII, nA and nXII), B6 subgroup of the dorsal raphe, Barrington's nucleus, and a small subset of neurons in the nucleus of solitary tract. In contrast to Met, neither full-length nor known splice variants of Hgf were localized in the prenatal brainstem. RT-PCR revealed Hgf expression in target tissues of Met-expressing brainstem neurons, suggesting that MET in these neurons may be activated by HGF from peripheral sources. Together, these data suggest that MET signaling may influence the development of neurons that are involved in central regulation of gastrointestinal function, tongue movement, swallowing, speech, stress and mood.
authors.affiliation: Department of Cell and Neurobiology, Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, Calif. 90089, USA.
authors.forename: Hsiao-Huei
authors.initials: HH
authors.lastname: Wu
authors.forename: Pat
authors.initials: P
authors.lastname: Levitt
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000196:embryology* / Q000378:metabolism; D003391:Cranial Nerves / Q000166:cytology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D020547:Lateral Ventricles / Q000196:embryology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology; D010870:Pineal Gland / Q000196:embryology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011903:Raphe Nuclei / Q000196:embryology* / Q000378:metabolism
chemical_list: C553307:HGF protein, mouse; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met
references.citation: Cereb Cortex. 2011 Jul;21(7):1613-26
references.pmid: 21127014
references.citation: Mol Cell Neurosci. 1996;8(4):242-57
references.pmid: 9000439
references.citation: Dev Med Child Neurol. 2012 Jan;54(1):23-9
references.pmid: 22142282
references.citation: Brain Res. 1993 Oct 8;624(1-2):188-98
references.pmid: 8252391
references.citation: Trends Cell Biol. 1998 Oct;8(10):404-10
references.pmid: 9789329
references.citation: J Cell Biol. 1993 Apr;121(1):145-54
references.pmid: 8384622
references.citation: Neuron. 1996 Dec;17(6):1157-72
references.pmid: 8982163
references.citation: J Cell Biol. 1996 May;133(3):709-18
references.pmid: 8636243
references.citation: Cancer Metastasis Rev. 2008 Mar;27(1):85-94
references.pmid: 18175071
references.citation: Brain Res. 1991 May 17;549(1):95-105
references.pmid: 1893257
references.citation: J Comp Neurol. 2010 Nov 1;518(21):4463-78
references.pmid: 20853516
references.citation: Development. 2003 Dec;130(26):6635-42
references.pmid: 14627719
references.citation: Pediatrics. 2009 Mar;123(3):1018-24
references.pmid: 19255034
references.citation: EMBO J. 1992 Jul;11(7):2503-10
references.pmid: 1321034
references.citation: Ciba Found Symp. 1993;172:5-21; discussion 21-9
references.pmid: 8491094
references.citation: J Comp Neurol. 2009 Apr 10;513(5):511-31
references.pmid: 19226509
references.citation: Nat Neurosci. 2010 Jan;13(1):133-40
references.pmid: 20023653
references.citation: Cytokine. 2001 May 7;14(3):170-6
references.pmid: 11396995
references.citation: Neuro Oncol. 2005 Oct;7(4):436-51
references.pmid: 16212809
references.citation: Nature. 1995 Feb 23;373(6516):699-702
references.pmid: 7854452
references.citation: Histochem Cell Biol. 2007 Dec;128(6):541-50
references.pmid: 17899157
references.citation: J Neurodev Disord. 2011 Sep;3(3):282-92
references.pmid: 21509596
references.citation: J Biol Chem. 2004 Jul 9;279(28):28970-8
references.pmid: 15123705
references.citation: Nature. 1995 Aug 31;376(6543):768-71
references.pmid: 7651534
references.citation: J Neurosci. 2011 Aug 3;31(31):11144-58
references.pmid: 21813676
references.citation: Experientia. 1964 Jul 15;20(7):398-9
references.pmid: 5856530
references.citation: Dev Biol. 2009 Nov 1;335(1):78-92
references.pmid: 19732764
references.citation: Eur J Biochem. 1991 Apr 10;197(1):15-22
references.pmid: 1826653
references.citation: Ann Neurol. 2007 Sep;62(3):243-50
references.pmid: 17696172
references.citation: Autism Res. 2012 Apr;5(2):101-8
references.pmid: 22511450
references.citation: Neuron. 2003 Jan 23;37(2):233-47
references.pmid: 12546819
references.citation: Pediatr Surg Int. 2011 Apr;27(4):353-8
references.pmid: 20697898
references.citation: Nat Rev Neurosci. 2001 Sep;2(9):611-23
references.pmid: 11533729
references.citation: Acta Neurol Scand. 2002 Aug;106(2):99-103
references.pmid: 12100369
references.citation: J Neurosci. 2010 Sep 15;30(37):12414-23
references.pmid: 20844136
references.citation: Nucleic Acids Res. 2012 Jan;40(Database issue):D1016-22
references.pmid: 22139918
references.citation: Biol Psychiatry. 2010 Apr 1;67(7):602-7
references.pmid: 19932467
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16834-9
references.pmid: 17053076
references.citation: J Comp Neurol. 1990 Mar 22;293(4):540-80
references.pmid: 1691748
references.citation: Nat Neurosci. 2009 Dec;12(12):1534-41
references.pmid: 19915564
references.citation: Prog Brain Res. 1973;40(0):53-65
references.pmid: 4802670
references.citation: Annu Rev Med. 2009;60:367-80
references.pmid: 19630577
references.citation: Mol Cell Biol. 1998 Mar;18(3):1275-83
references.pmid: 9488442
references.citation: Nat Rev Mol Cell Biol. 2010 Dec;11(12):834-48
references.pmid: 21102609
references.citation: Nature. 1989 Nov 23;342(6248):440-3
references.pmid: 2531289
references.citation: Development. 2006 Apr;133(8):1575-85
references.pmid: 16556916
references.citation: J Cell Biol. 1993 Oct;123(1):223-35
references.pmid: 8408200
references.citation: Nature. 1987 May 21-27;327(6119):239-42
references.pmid: 2952888
references.citation: Development. 2000 Apr;127(8):1751-66
references.pmid: 10725250
references.citation: J Comp Neurol. 1960 Apr;114:161-87
references.pmid: 13836517
references.citation: Nature. 2011 May 25;474(7351):380-4
references.pmid: 21614001
references.citation: Infant Child Dev. 2011 Feb;20(1):106-118
references.pmid: 21516219
references.citation: Neurosci Lett. 1987 Sep 23;80(2):197-201
references.pmid: 3683977
references.citation: J Neurosci. 2007 May 2;27(18):4902-9
references.pmid: 17475798
references.citation: Ann Neurol. 2005 Jan;57(1):67-81
references.pmid: 15546155
references.citation: J Biol Chem. 1996 May 31;271(22):13110-5
references.pmid: 8662798
references.citation: J Chem Neuroanat. 2011 Jul;41(4):266-80
references.pmid: 21658442
references.citation: J Cell Sci. 1985 Aug;77:209-23
references.pmid: 3841349
references.citation: Nat Rev Neurosci. 2011 Jul 13;12(8):453-66
references.pmid: 21750565
references.citation: Development. 2003 Mar;130(6):1113-22
references.pmid: 12571103
references.citation: Anat Embryol (Berl). 1978 Sep 27;154(3):241-51
references.pmid: 707816
references.citation: Brain Res. 1989 Jul 17;492(1-2):99-115
references.pmid: 2752312
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22462-7
references.pmid: 20080794
references.citation: Autism Res. 2009 Aug;2(4):232-6
references.pmid: 19681062
references.citation: Am J Hum Genet. 2009 Jul;85(1):25-39
references.pmid: 19576567
references.citation: J Neurosci. 2011 Apr 13;31(15):5855-64
references.pmid: 21490227
references.citation: J Autism Dev Disord. 2010 Mar;40(3):358-70
references.pmid: 19885725
references.citation: Nat Rev Mol Cell Biol. 2003 Dec;4(12):915-25
references.pmid: 14685170
references.citation: Physiol Behav. 2002 Dec;77(4-5):737-42
references.pmid: 12527028
references.citation: Cancer Res. 1984 Jan;44(1):1-10
references.pmid: 6418375
references.citation: Autism Res. 2008 Jun;1(3):159-68
references.pmid: 19360663
references.citation: J Auton Nerv Syst. 2000 Mar 15;79(2-3):117-28
references.pmid: 10699642
references.citation: Diabetes. 2010 Dec;59(12):3108-16
references.pmid: 20841608
references.citation: Science. 1991 Nov 29;254(5036):1382-5
references.pmid: 1720571
references.citation: J Cell Physiol. 2007 Nov;213(2):316-25
references.pmid: 17607709
references.citation: Neuroscience. 1990;36(1):217-37
references.pmid: 2215919
references.citation: J Dev Behav Pediatr. 2011 Jun;32(5):351-60
references.pmid: 21555957
references.citation: FEBS Lett. 1987 Nov 30;224(2):311-6
references.pmid: 3319692
references.citation: Annu Rev Med. 2011;62:381-96
references.pmid: 21090962
references.citation: Nature. 1984 Sep 6-11;311(5981):29-33
references.pmid: 6590967