Bmp5/7 in concert with the mid-hindbrain organizer control development of noradrenergic locus coeruleus neurons

• Published in: Molecular and cellular neuroscience 2010-09, Vol.45 (1), p.1-11
• Main Authors: Tilleman, Hadas, Hakim, Vicky, Novikov, Orna, Liser, Keren, Nashelsky, Limor, Di Salvio, Michela, Krauthammer, Mark, Scheffner, Oren, Maor, Ido, Mayseless, Oded, Meir, Inbal, Kayam, Galya, Sela-Donenfeld, Dalit, Simeone, Antonio, Brodski, Claude
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Bmp5; Bmp7; Bone Morphogenetic Protein 5 - metabolism; Bone Morphogenetic Protein 7 - metabolism; Bone morphogenetic proteins; Development; Fibroblast Growth Factor 8 - genetics; Fibroblast Growth Factor 8 - metabolism; Hindbrain; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Isthmic organizer; Locus coeruleus; Locus Coeruleus - cytology; Locus Coeruleus - embryology; Locus Coeruleus - metabolism; Mesencephalon - cytology; Mesencephalon - physiology; Mice; Mice, Knockout; Mid-hindbrain organizer; Neurons - cytology; Neurons - physiology; Noradrenaline; Norepinephrine - metabolism; Otx Transcription Factors - genetics; Otx Transcription Factors - metabolism; Otx2; Rhombencephalon - cytology; Rhombencephalon - physiology; Stem Cells - cytology; Stem Cells - physiology
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2010.05.003

The locus coeruleus (LC) which is the major noradrenergic nucleus in the brain develops under the influence of Bmps secreted by the roof plate and Fgf8 emitted from the mid-hindbrain organizer. We studied the development of the LC in different Bmp mouse mutants and report the absence of this nucleus in Bmp5−/−;Bmp7−/− double knockouts. Notably, genes marking organizers and neuronal populations adjacent to the LC precursor field are unperturbed in Bmp5−/−;Bmp7−/− animals. In addition, we found that in En1+/Otx2 mutants in which the caudal Otx2 expression domain and thereby the mid-hindbrain organizer are shifted caudally, LC neurons are concomitantly reduced along with Bmp5/7. Complementing these results, Otx1−/−;Otx2+/− mutants, in which the mid-hinbrain organizer is shifted rostrally, show a rostrally extended Bmp5 expression area and an increase in LC neurons. Taken together, our data indicate that LC development requires either Bmp5 or Bmp7, and one is able to compensate for the loss of the other. In addition, we conclude that the position of the mid-hindbrain organizer determines the size of the LC and propose that Bmp5/7 play an important role in mediating this organizer function.