Segmental arithmetic: summing up the Hox gene regulatory network for hindbrain development in chordates.

Organization and development of the early vertebrate hindbrain are controlled by a cascade of regulatory interactions that govern the process of segmentation and patterning along the anterior-posterior axis via Hox genes. These interactions can be assembled into a gene regulatory network that provides a framework to interpret experimental data, generate hypotheses, and identify gaps in our understanding of the progressive process of hindbrain segmentation. The network can be broadly separated into a series of interconnected programs that govern early signaling, segmental subdivision, secondary signaling, segmentation, and ultimately specification of segmental identity. Hox genes play crucial roles in multiple programs within this network. Furthermore, the network reveals properties and principles that are likely to be general to other complex developmental systems. Data from vertebrate and invertebrate chordate models are shedding light on the origin and diversification of the network. Comprehensive cis-regulatory analyses of vertebrate Hox gene regulation have enabled powerful cross-species gene regulatory comparisons. Such an approach in the sea lamprey has revealed that the network mediating segmental Hox expression was present in ancestral vertebrates and has been maintained across diverse vertebrate lineages. Invertebrate chordates lack hindbrain segmentation but exhibit conservation of some aspects of the network, such as a role for retinoic acid in establishing nested Hox expression domains. These comparisons lead to a model in which early vertebrates underwent an elaboration of the network between anterior-posterior patterning and Hox gene expression, leading to the gene-regulatory programs for segmental subdivision and rhombomeric segmentation. WIREs Dev Biol 2017, 6:e286. doi: 10.1002/wdev.286 For further resources related to this article, please visit the WIREs website.