To understand vertebrate brain development we must determine how the cells of the simple, two-dimensional anterior neural plate are signalled to undergo complex reorganisation in to the elaborately structured, three-dimensional forebrain. To address this, I have collected time-lapse 3D movies of brain development in the optically transparent zebrafish embryo. I used these movies to accurately track the paths of many hundreds of cells representing the important cell territories of the brain, and so constructed dynamic, high-resolution fate maps of their transformations. My findings in wild-type embryos challenge the accepted model of forebrain folding. The resolution of bilateral eyes is not, as believed, achieved by the anterior-ward progression of the ventral diencephalon (hypothalamus) in the form of a neural keel, through the initially monocular eye field. The neural keel is actually formed by the hypothalamus moving deep than anterior-wards, subducting but not reshaping, more anterior progenitors of the dorsal forebrain (telencephalon) and medial eye field. In a novel observation, I can show that the separation of bilateral eyes occurs subsequent to this, coincident with the anterior-ward movement of dorsal diencephalic cells along the neural tube. I then used this new detailed model of normal development to address the causes of cyclopia – one consequence of the common human neural tube defect, holoprosencephaly (HPE). My analysis of time-lapse movies of animals with reduced <i>Nodal </i>or <i>Wnt11</i> signalling – modelling HPE, identified two distinct morphogenetic events, whose failure can cause cyclopia. Under conditions of reduced <i>Nodal</i> signalling, cyclopia occurs because the cells moving deep to form the ventral midline are erroneously derived from eye territories anterior to the normal presumptive hypothalamus. In contrast, in mutant embryos with reduced <i>Wnt11</i> signalling, cyclopia<i> </i>results from a reduced anterior-ward extension and movement of the future dorsal diencephalons, causing incomplete evagination of the optic lobes.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:598850 |
| Date | January 2005 |
| Creators | England, S. J. |
| Publisher | University of Cambridge |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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