Drossopoulou, Garyfalia; (1998) The role of Sonic hedgehog in patterning the chick embryonic limb. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis investigates the cellular and molecular basis of patterning of the antero-posterior axis of the chick limb by Sonic Hedgehog (Shh). Shh is expressed in the polarizing region, which is localised at the posterior margin of the limb bud. Shh expression is stable when the polarizing region is transplanted to the anterior margin of another chick limb bud and additional digits are specified, but Shh is not induced in host tissue. Application of Shh at the anterior of the chick limb bud also gives rise to digit duplications. High Shh concentrations result in shoulder girdle defects mediated by activation of Bmps. Shh acts in a dose dependent manner specifying digits in an anterior to posterior sequence, with anterior digits being specified first. DiI and DiA labelling shows that the fate of cells up to 300?m away from the Shh source can be influenced and cells that would not normally contribute to digit formation, can now give rise to an extra digit 2 or 3 according to the length of time that they have been exposed to Shh. Molecules such as Bmp-2, Fgf-4, Hoxd-13 and Hoxa-13 involved in antero-posterior patterning are induced by Shh at 16 hours after application. The tumor suppressor gene patched (ptc), the putative receptor for Shh is induced as early as 2-4 hours indicating a rather fast response. However, it is not until 24 hours after Shh application that irreversible digit pattern duplications are produced and this correlates with irreversible ectopic Bmp-2 expression. Application of Bmp-2, at 16 hours can not replace the effects of Shh, but can enhance significantly the polarizing activity, especially if combined with Fgf-4. In talpid3 chick mutant, ptc is not expressed at high levels even after exogenous application of Shh, suggesting that induction of Bmp-2 and Hoxd-13 is independent of ptc. A COS cell line expressing a membrane tethered Shh construct was prepared but these cells did not produce pattern changes when grafted to chick wing buds.

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