Studies in humans have shown that 1 in 1800 infants are born with limb deficiencies and that 9% of these also suffers from renal abnormalities. Classification of these limb abnormalities revealed that the renal defects commonly associate with limb deficiencies such as micromelia (44%), amelia (18%) and radial/tibial (preaxial) deficiencies (27%). Additionally, experimental evidence has shown that the mesonephros, an important component of the primitive urogenital system, also could be responsible for inducing and maintaining limb development. These observations imply the existence of a developmental link between limb induction and early kidney development. However, this remains controversial since other experiments show that the mesonephros is not required for limb development. The work described in this thesis was prompted by the observation, that the mouse mutants dominant hemimelia (Dh) and luxate (Ix) disrupt both limb induction and kidney development. Furthermore, both mutants display preaxial abnormalities such as Polydactyly, oligodactyly and tibial hemimelia of the hindlimbs. In addition Dh also causes asplenia, microgastria, small pancreas, gut atresia. The studies presented here show that the hindlimbs in Dh animals are shifted 2-3 segments anteriorly coinciding with a lumbar-sacral transformation of the axial skeleton. In situ hybridisation shows that the anterior boundary of HoxclO in the flank mesenchyme has moved anteriorly in Dh embryos while the expression of HoxalO and HoxdlO appear to be unaffected. The spinal nerves innervating the hindlimbs also respond to the shift of the limbs. Analysis of the urogenital phenotype shows that the effect Dh has on the kidney abnormalities is indirect. It appears that the hydronephrosis observed in Dh mice is caused by blockage of the ureter, however, it is possible that this blockage is related to misexpression to HoxclO. Efforts were therefore made to determine if other traits related to the Dh mutation was caused by ectopic HoxclO expression, however, this does not appear to be the case. Nevertheless these studies led to the identification of a novel anatomical structure, the splanchnic mesothelial ridge (SMR). The SMR consists of a thickened mesothelium on the left side of the spleno-pancreatic region, which is required for asymmetric growth. In Dh mice the SMR is absent and as a result the splenopancreatic region asymmetric growth is impaired. The asplenic phenotype is also related to the absence of the SMR.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:726378 |
| Date | January 2003 |
| Creators | Hecksher-Sørensen, Jacob |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/24690 |
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