Altered neuronal lineages in the facial ganglia of Hoxa2 mutant mice.

摘要

Neurons of cranial sensory ganglia are derived from the neural crest cells (NCCs) and ectodermal placodes, while the glial cells are exclusively derived from the crest. Neural crest and placodal cells generate different portions of neurons in different ganglia. For example, crest cells of the second branchial arch (BA2) generate very few neurons in facial ganglion and none in the vestibuloacoustic ganglion, but in other branchial arches crest cells generate many sensory neurons. Until now, the mechanisms that control the relative contributions of these sources in different ganglia have not been well understood.;HOX genes play critical roles in controlling the behavior of neural crest cells at different axial levels in craniofacial tissues. A striking example is the requirement of Hoxa2 function in neural crest that arise from the fourth rhombomere (r4) of the hindbrain to form the mesenchyme of the second branchial arch. Unexpectedly, we found that the facial ganglia of Hoxa2 mutant mice contain a large population of crest-derived neurons that are not present in wild-type embryos, suggesting that Hoxa2 normally represses the neurogenic potential of second arch crest cells.;One paradigm that was used to test this hypothesis was the overexpression of Hoxa2 in cultures of P19 embryonal carcinoma cells. In high density cultures, P19 cells can spontaneously differentiate into neurons as detected by the expression of PGP9.5, a pan-neuronal marker. After overexpressing Hoxa2 in P19 cells, we detected a reduced frequency of spontaneous neuronal differentiation, but only when P19 cells were co-transfected with two Hox cofactors, Pbx1 and Meis1. Interestingly, the inhibitory function of Hoxa2 in neural differentiation could be antagonized by co-expressing one of Hox3 paralogs, Hoxd3.;Finally, ectopic expression of Hoxa2 and its cofactors in chick neural crest cells populating the trigeminal ganglion also reduced the frequency of neurogenesis by neural crest cells in the intact embryo. These data suggest an unanticipated role for HOX genes in controlling the neurogenic potential of at least some cranial neural crest cells, and suggest their possible roles in modulating neuronal differentiation by other populations of crest cells warrants further scrutiny.