The prospect of using cell replacement therapies has raised the key issue of whether elucidation of developmental pathways can facilitate the generation of therapeutically important cell types from stem cells. Here we show that the homeodomain proteins Lmx1a and Msx1 function as determinants of midbrain dopamine neurons, cells that degenerate in patients with Parkinson's disease. Lmx1a is sufficient and required to trigger dopamine cell differentiation. An early activity of Lmx1a is to induce the expression of Msx1, which complements Lmx1a by inducing the proneural protein Ngn2 and neuronal differentiation. Importantly, expression of Lmx1a in embryonic stem cells results in a robust generation of dopamine neurons with a "correct" midbrain identity. These data establish that Lmx1a and Msx1 are critical intrinsic dopamine-neuron determinants in vivo and suggest that they may be essential tools in cell replacement strategies in Parkinson's disease.

Regeneration of appendages is frequent among invertebrates as well as some vertebrates. However, in mammals this has been largely relegated to digit tip regeneration, as found in mice and humans. The regenerated structures are formed from a mound of undifferentiated cells called a blastema, found just below the site of amputation. The blastema ultimately gives rise to all of the tissues in the regenerate, excluding the epidermis, and has classically been thought of as a homogenous pool of pluripotent stem cells derived by dedifferentiation of stump tissue, although this has never been directly tested in the context of mammalian digit tip regeneration. Successful digit tip regeneration requires that the level of amputation be within the nail bed and depends on expression of Msx1. Because Msx1 is strongly expressed in the nail bed mesenchyme, it has been proposed that the Msx1-expressing cells represent a pluripotent cell population for the regenerating digit. In this report, we show that Msx1 is dynamically expressed during digit tip regeneration, and it does not mark a pluripotent stem cell population. Moreover, we show that both the ectoderm and mesoderm contain fate-restricted progenitor populations that work in concert to regenerate their own lineages within the digit tip, supporting the hypothesis that the blastema is a heterogeneous pool of progenitor cells.

A new mouse Hox locus, Hox‐7, is defined on chromosome 5 by a gene homologous to the Drosophila gene msh, which contains a homeobox sequence distantly related to that of Antennapedia. By in situ hybridization, expression of Hox‐7 is detected in the neural fold of embryos, and also in cephalic neural crest. In addition, expression takes place in the developing valves of the embryonic heart. Mandibular and hyoid arches are strongly labelled, expression becoming restricted to the most distal part of mouth and face processes as development proceeds. Intense labelling is also observed in developing limb buds, in the distal region which has been shown to be essential for limb morphogenesis. The pronounced accumulation and regional localization of Hox‐7 transcripts in mandibular and limb processes point to a specific morphogenetic role for this mouse homeobox gene.

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