Fig. 5. Proposed model for regulation of hindbrain, inner ear and neural crest development by Hoxa1.

Our data suggests that Hoxa1 influences hindbrain patterning through Hnf1b, which in turn activates Krox20. It also suggests that Hoxa1 might regulate neural crest development, through Foxd3, Zic1 and Hnf1b, which could be the reason for the outflow tract defects in humans. In inner ear development, Hoxa1 acts upstream of Pax8 and Fgfr3. In addition, Hoxa1 might regulate Lhx5 expression in reticulospinal neuron precursors, which could contribute to the respiratory defects in Hoxa1 knockout mice. Whether the above effects are direct or through Hoxa1’s influence on hindbrain patterning remains to be shown (as highlighted by the dotted arrows) and will be the ground for future investigations.