Target-dependent inhibition of sympathetic neuron growth via modulation of a BMP signaling pathway.
Target-derived factors modulate many aspects of peripheral neuron development including neuronal growth, survival, and maturation. Less is known about how initial target contact regulates changes in gene expression associated with these developmental processes. One early consequence of contact between growing sympathetic neurons and their cardiac myocyte targets is the inhibition of neuronal outgrowth. Analysis of neuronal gene expression following this contact revealed coordinate regulation of a bone morphogenetic protein (BMP)-dependent growth pathway in which basic helix-loop-helix transcription factors and downstream neurofilament expression contribute to the growth dynamics of developing sympathetic neurons. BMP2 had dose-dependent growth-promoting effects on sympathetic neurons cultured in the absence, but not the presence, of myocyte targets, suggesting that target contact alters neuronal responses to BMP signaling. Target contact also induced the expression of matrix Gla protein (MGP), a regulator of BMP function in the vascular system. Increased MGP expression inhibited BMP-dependent neuronal growth and MGP expression increased in sympathetic neurons during the period of target contact in vivo. These experiments establish MGP as a novel regulator of BMP function in the nervous system, and define developmental transitions in BMP responses during sympathetic development.
Moon
Jung-Il
JI
Department of Biology, National Center for Behavioral Genomics, Brandeis University, Waltham, MA 02254-9110, USA.
Birren
Susan J
SJ
D000818:Animals; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002450:Cell Communication; D002478:Cells, Cultured; D018920:Coculture Techniques; D017931:DNA Primers / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D016501:Neurites / Q000378:metabolism / Q000648:ultrastructure; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013564:Sympathetic Nervous System / Q000166:cytology / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D000097568:Matrix Gla Protein
D051792:Basic Helix-Loop-Helix Proteins; D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D016900:Neurofilament Proteins; D012333:RNA, Messenger; D000097568:Matrix Gla Protein; C044882:neurofilament protein L; C061195:neurofilament protein M