Nittenberg, Ronald; (1997) Cell Signalling in Limb Development and Hindbrain Segmentation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Receptor protein tyrosine kinases are important for the regulation of cell growth, differentiation and pattern formation. To date 14 subfamilies are known, of which the Eph subfamily is the largest. In this thesis I examine the regulation of expression of the Eph-related Cek-8 gene during limb development and hindbrain segmentation. Cek-8 was found to be expressed in the mesenchyme at the tip of chick limb buds with high levels of transcripts posteriorly and apically but fading out anteriorly. Expression of Cek-8 in distal mesenchyme was found to be regulated by signals from the apical ridge, which could be substituted by FGF, and also by signals from the polarising region and by retinoic acid. Cek-8 expression was uniform across the antero-posterior axis of limb buds in talpid3, a chick mutant with polydactylous limbs with up to 7-8 morphologically similar digits. These findings indicate that Cek-8 expression responds to regulatory signals during limb patterning and suggest that this receptor tyrosine kinase may have a role in coordinating responses to signals in the progress zone of early buds. Later on in limb development, Cek-8 expression was found to be associated with cell condensations that form tendons and their attachments to cartilage rudiments and then in developing feather buds. Cek-8 is also expressed in the developing hindbrain in rhombomeres 3 and 5. Local treatment with retinoic acid led to a partly unsegmented hindbrain and this loss of segmentation (or boundaries) was found to be preceded by changes in segmental gene expression of Cek-8. Loss of boundaries was always correlated with changes in Cek-8 expression. Changes in Hox (homeobox containing genes) gene expression were only apparent after morphological changes occurred and did not seem to impose a new identity on neural precursor cells. Normally, cells from adjacent rhombomeres do not mix and no substantial cell mixing could be detected even in the absence of a physical boundary. Possible roles of Cek-8 during hindbrain segmentation are discussed.

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