Gavalas Anthony, Ruhrberg Christiana, Livet Jean, Henderson Christopher E, Krumlauf Robb
Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Development. 2003 Dec;130(23):5663-79. doi: 10.1242/dev.00802. Epub 2003 Oct 1.
Hox genes are instrumental in assigning segmental identity in the developing hindbrain. Auto-, cross- and para-regulatory interactions help establish and maintain their expression. To understand to what extent such regulatory interactions shape neuronal patterning in the hindbrain, we analysed neurogenesis, neuronal differentiation and motoneuron migration in Hoxa1, Hoxb1 and Hoxb2 mutant mice. This comparison revealed that neurogenesis and differentiation of specific neuronal subpopulations in r4 was impaired in a similar fashion in all three mutants, but with different degrees of severity. In the Hoxb1 mutants, neurons derived from the presumptive r4 territory were re-specified towards an r2-like identity. Motoneurons derived from that territory resembled trigeminal motoneurons in both their migration patterns and the expression of molecular markers. Both migrating motoneurons and the resident territory underwent changes consistent with a switch from an r4 to r2 identity. Abnormally migrating motoneurons initially formed ectopic nuclei that were subsequently cleared. Their survival could be prolonged through the introduction of a block in the apoptotic pathway. The Hoxa1 mutant phenotype is consistent with a partial misspecification of the presumptive r4 territory that results from partial Hoxb1 activation. The Hoxb2 mutant phenotype is a hypomorph of the Hoxb1 mutant phenotype, consistent with the overlapping roles of these genes in facial motoneuron specification. Therefore, we have delineated the functional requirements in hindbrain neuronal patterning that follow the establishment of the genetic regulatory hierarchy between Hoxa1, Hoxb1 and Hoxb2.
Hox基因在发育中的后脑节段身份分配中起重要作用。自调控、交叉调控和旁调控相互作用有助于建立和维持它们的表达。为了了解这种调控相互作用在多大程度上塑造了后脑的神经元模式，我们分析了Hoxa1、Hoxb1和Hoxb2突变小鼠的神经发生、神经元分化和运动神经元迁移。这种比较表明，在所有三个突变体中，r4中特定神经元亚群的神经发生和分化以类似的方式受损，但严重程度不同。在Hoxb1突变体中，源自假定r4区域的神经元被重新指定为类似r2的身份。源自该区域的运动神经元在迁移模式和分子标记表达方面都类似于三叉神经运动神经元。迁移的运动神经元和驻留区域都发生了与从r4身份转变为r2身份一致的变化。异常迁移的运动神经元最初形成异位核，随后被清除。通过引入凋亡途径的阻断可以延长它们的存活时间。Hoxa1突变体表型与由于部分Hoxb1激活导致的假定r4区域的部分错误指定一致。Hoxb2突变体表型是Hoxb1突变体表型的亚效等位基因，与这些基因在面部运动神经元特化中的重叠作用一致。因此，我们已经描绘了在Hoxa1、Hoxb1和Hoxb2之间建立遗传调控层次结构后，后脑神经元模式形成中的功能需求。
