Specific and redundant functions of the paralogous Hoxa-9 and Hoxd-9 genes in forelimb and axial skeleton patterning.

Using gene targeting, we have produced mice with a disruption of Hoxa-9 or Hoxd-9, two paralogous Abdominal B-related genes. During embryogenesis, these genes are expressed in limb buds and along the vertebral axis with anterior expression boundaries at the level of prevertebra #20 for Hoxa-9 and #23 for Hoxd-9. Skeletal analysis revealed homeotic transformations corresponding to anteriorisations of vertebrae #21 to #25 (L1 to L5) in the lumbar region of Hoxa-9-/- mutants; vertebrae #23 to #25 (L3 to L5) in the lumbar region together with vertebrae #28, #30 and #31 (S2, S4 and Ca1) in the sacrum and tail were anteriorized in Hoxd-9-/- mutants. Thus, anteriorisation of vertebrae #23 to #25 were common to both phenotypes. Subtle forelimb (but not hindlimb) defects, corresponding to a reduction of the humerus length and malformation of its deltoid crest, were also observed in Hoxd-9-/-, but not in Hoxa-9-/-, mutant mice. By intercrosses between these two lines of mutant mice, we have produced Hoxa-9/Hoxd-9 double mutants which exhibit synergistic limb and axial malformations consisting of: (i) an increase of penetrance and expressivity of abnormalities present in the single mutants, and (ii) novel limb alterations at the level of the forelimb stylopod and additional axial skeleton transformations. These observations demonstrate that the two paralogous genes Hoxa-9 and Hoxd-9 have both specific and redundant functions in lumbosacral axial skeleton patterning and in limb morphogenesis at the stylopodal level. Taken all together, the present and previously reported results show that disruption of different Hox genes can produce similar vertebral transformations, thus supporting a combinatorial code model for specification of vertebral identity by Hox genes.

Restricted expression of the ron gene encoding the macrophage stimulating protein receptor during mouse development.

The human ron gene codes for a transmembrane protein tyrosine kinase which is a receptor for the macrophage stimulating protein. The ron receptor, together with the hepatocyte growth factor/scatter factor receptor encoded by the proto-oncogene met, and the product of the c-sea proto-oncogene, make up a family of structurally related receptors. We have cloned murine ron cDNA sequences and used them as probes for in situ hybridization and Northern blot experiments. We show that ron gene expression occurs relatively late in development, and is much more restricted than that of the met gene. ron gene expression is detected in specific areas of the central and the peripheric nervous system, as well as in discrete cells in developing bones, and in the glandular epithelia along the digestive tract.