Figure 8. Hox Cross-Repression and Control of Motor Neuron Topography.

(A) Summary of alterations in MN organization and muscle innervation in Hoxc9 mutants. HMC MNs are lost and are transformed to an LMC identity. A subset of ectopic thoracic LMC MNs express Pea3 or Scip and project to intercostal muscle. Other motor pool fates may also be acquired by Hox derepression (indicated in gray). As a consequence of the reduction of Scip⁺ MNs at caudal brachial levels, median and ulnar nerve projections are profoundly reduced. (B) Hoxc9 is a key repressor of brachial Hox genes. In thoracic MNs, Hoxc9 represses brachial Hox genes by directly binding regulatory regions. The efficacy of Hoxc9 repression appears to be graded, where Hox4–6 genes are strongly repressed, while Hox7–8 gene repression is weaker. Hox10 genes are excluded by the distinct mechanism, likely involving H3K27 methylation-dependent silencing. At brachial levels, an intrasegmental Hox repressor network involving interactions amongst Hox4–8 genes determines pool fate on a cell-by-basis (Dasen et al., 2005). At the brachial-thoracic boundary Hoxc6 and Hoxc8 promote LMC fates, defined by high FoxP1 levels and RALDH2. Low levels of Hoxc9 repress Hoxc6 expression to specify the Scip⁺ LMC pool whereas MNs maintaining both Hoxc6 and Hoxc8 become Pea3⁺. Pool clustering occurs after MNs have acquired a specific identity.