Isthmic organizer
Theisthmic organizer,oristhmus organizer,also known as themidbrain−hindbrain boundary(MHB), is a secondary organizer region that develops at the junction of themidbrainandmetencephalon(embryonichindbrain).[1]The MHBexpressessignaling moleculesthat regulate thedifferentiationand patterning of the adjacentneuroepithelium.This allows for the development of themidbrainandhindbrainas well as the specification ofneuronalsubtypes in these regions.[2]The fact that the MHB is sufficient for the development of the mid and hindbrain was shown in anexperimentwherequailMHBcellstransplanted into theforebrainof achickwere able to induce anectopicmidbrain andcerebellum.[3]
Development of the isthmus (MHB)
[edit]The development and location of the MHB is mediated by thetranscription factorsOtx2andGbx2.[2]Otx2isexpressedin theanteriorneural tubeand cells in theposteriorneural tube expressGbx2.[3]These twohomeodomain transcription factorsare activated byIrx1and then cross inhibit one another in the developingcentral nervous system(CNS).[3]This leads to the creation of a defined boundary that becomes the isthmic organizer region after the neural tube closes.[2]
Signaling molecules
[edit]
The usual combined expression pattern of all involvedsignaling moleculesis necessary for the formation and maintenance of the MHB as well as the development of the midbrain and cerebellum. The following three signaling molecules act in an interconnected network to set up and maintain the MHB.[3]Loss of any one of them leads to not only decreased expression of the other two but will also lead to partial or complete loss of the midbrain and hindbrain.
Fgf8
[edit]The interaction betweenOtx2andGbx2at the MHB results in the expression offibroblast growth factor 8 (Fgf8).Out of the knownisoformsofFgf8,Fgf8aandFgf8bhave been shown to be expressed at the isthmic organizer withFgf8bbeing prevalent.[1]Fgf8expression leads to the activation ofEn1in cells that express bothIrx1andOtx2.
Fgf8 was shown to be an organizing molecule in the MHB through an experiment where an Fgf8-loaded bead was placed on a more anterior region of the neural tube.[3]This resulted in the formation of a new ectopic MHB and showed that Fgf8 could mimic the activity of the MHB to induce the formation of midbrain and hindbrain structures from the anteriortissues.
Fgf8 signaling at the MHB combined withOtx2expression inducesdopaminergicneurondifferentiation in the midbrain. On the other hand, when Fgf8 expression spreads into theGbx2expressing hindbrain, it leads toserotonergicneuron differentiation. Later on inembryonic development,Fgf8expression localizes to therostralmostGbx2expressing cells (caudal region of the MHB) in the neural tube.[4]
Wnt1
[edit]Wnt1is mainly expressed in the entire midbrain (Otx2expressing cells) at first.[5]Once the midbrain/hindbrain boundary has formed,Wnt1expression localizes to theroof plateof the neural tube and to the posterior region of the midbrain. At the MHB, Wnt1 plays a role in cell proliferation and also maintains theFGF8expression.
Engrailed-1
[edit]The transcription factorEn1is expressed in the MHB. In cells that express bothOtx2andIrx1,En1is activated by Fgf8 signaling.En1expression in cells that express bothPax2andOtx2leads to a midbrain identity/fate.[5]
References
[edit]- ^abNakamura, H; Watanabe, Y (2005)."Isthmus organizer and regionalization of the mesencephalon and metencephalon".The International Journal of Developmental Biology.49(2–3): 231–5.doi:10.1387/ijdb.041964hn.PMID15906236.
- ^abcSiegelbaum, Steven A., and A. James Hudspeth. Principles of neural science. Eds. Eric R. Kandel, James H. Schwartz, and Thomas M. Jessell. Vol. 5. New York: McGraw-hill, 2013.[pages needed]
- ^abcdeSanes, D; Reh, T; Harris, W (2012). "Chapter 2: Polarity and segmentation".Development of the nervous system(3rd ed.). Burlington, MA: Academic Press. pp. 23–48.ISBN9780080923208.
- ^Wurst, W; Bally-Cuif, L (February 2001). "Neural plate patterning: upstream and downstream of the isthmic organizer".Nature Reviews. Neuroscience.2(2): 99–108.doi:10.1038/35053516.PMID11253000.
- ^abNakamura, H; Katahira, T; Matsunaga, E; Sato, T (September 2005). "Isthmus organizer for midbrain and hindbrain development".Brain Research Reviews.49(2): 120–6.doi:10.1016/j.brainresrev.2004.10.005.PMID16111543.