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.
Bibliographical noteFunding Information:
We are grateful to Elizabeth J. Robertson (University of Oxford, UK) for her generous gift of Bmp6 −/− and Bmp7 −/− mutant mice and to Jean-François Brunet (École Normale Supérieure, Paris, France) for his generous gift of Phox2a antisera. This work was supported by research grants from the Israel Science Foundation grant No. 864/05 , the National Institute for Psychobiology in Israel — founded by the Charles E. Smith Family ( 7-2004-05 , 212-2007-08 ), and by the Israeli Ministry of Health , Chief Scientist's Office ( 3-00000-3546 ) to C. B.; the Italian Association for Cancer Research (AIRC) and the “Stem Cell Project” of Fondazione Roma to A.S.; the Israel Science Foundation grant 161/07 to D.S-D.
- Bone morphogenetic proteins
- Isthmic organizer
- Locus coeruleus
- Mid-hindbrain organizer