Retinoic acid alters hindbrain Hox code and induces transformation of rhombomeres 2/3 into a 4/5 identity
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Targeted disruption of the murine hox-A1 gene results in severe defects in the formation of the hindbrain and associated cranial ganglia and nerves. Carbocyanine dye injections were used to trace afferent and efferent projections to and from the hindbrain in hox-A1-/hox-A1- mutant mice. Defects were observed in the position of efferent neurons in the hindbrain and in their projection patterns. In situ hybridization was used to analyze the transcription pattern of genes expressed within specific rhombomeres. Krox-20, int-2 (fgf-3), and hox-B1 all display aberrant patterns of expression in hox-A1- mutant embryos. The observed morphological and molecular defects suggest that there are changes in the formation of the hindbrain extending from rhombomere 3 through rhombomere 8 including the absence of rhombomere 5. Also, motor neurons identified by their axon projection patterns which would normally be present in the missing rhombomere appear to be respecified to or migrate into adjacent rhombomeres, suggesting a role for hox-A1 in the specification of cell identity and/or cell migration in the hindbrain.
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Abstract In the hindbrain and the adjacent cranial neural crest (NC) cells of jawed vertebrates (gnathostomes), nested and segmentally-restricted domains of Hox gene expression provide a combinatorial Hox -code for specifying regional properties during head development. Extant jawless vertebrates, such as the sea lamprey (Petromyzon marinus), can provide insights into the evolution and diversification of this Hox -code in vertebrates. There is evidence for gnathostome-like spatial patterns of Hox expression in lamprey; however, the expression domains of the majority of lamprey hox genes from paralogy groups (PG) 1-4 are yet to be characterized, so it is unknown whether they are coupled to hindbrain segments (rhombomeres) and NC. In this study, we systematically describe the spatiotemporal expression of all 14 sea lamprey hox genes from PG1-PG4 in the developing hindbrain and pharynx to investigate the extent to which their expression conforms to the archetypal gnathostome hindbrain and pharyngeal hox- codes. We find many similarities in Hox expression between lamprey and gnathostome species, particularly in rhombomeric domains during hindbrain segmentation and in the cranial neural crest, enabling inference of aspects of Hox expression in the ancestral vertebrate embryonic head. These data are consistent with the idea that a Hox regulatory network underlying hindbrain segmentation is a pan vertebrate trait. We also reveal differences in hindbrain domains at later stages, as well as expression in the endostyle and in pharyngeal arch (PA) 1 mesoderm. Our analysis suggests that many Hox expression domains that are observed in extant gnathostomes were present in ancestral vertebrates but have been partitioned differently across Hox clusters in gnathostome and cyclostome lineages after duplication.
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This chapter discusses current understanding of hindbrain development with particular emphasis on the roles of Hox genes in mediating this process. The chapter is divided into three sections. The first section explores the properties of rhombomeres that influence how the neuronal architecture of the hindbrain is formed. The second examines the organization, expression patterns, and genetic function of Hox genes. The positional cues for patterning the head and neck appear to depend on the underlying embryonic organization of the central nervous system. The third section focuses on the neural crest, which is the conduit for transferring this positional information.
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During the last few years, the regionalization of the rostral-caudal axis has been extensively studied through treatments with RA and genetic manipulations of Hox-C genes. RA shifts several Hox expression boundaries rostrally, deletes anterior rhombomeres but expands the caudal ones, and induces homeotic transformations in the vertebral column. These phenotypes indicate that retinoids may act in a graded fashion in the A-P axis, with maximum activity caudally. This excludes forebrain and midbrain, which apparently depend on neither Hox-C genes nor RA modulations, at least during early development. The phenotypes resulting from ectopic overexpression and loss of function of Hox genes described so far show homeotic transformations in paraxial mesoderm derivatives but not in the neurectoderm. An explanation for this discrepancy implies that the paraxial mesoderm may be already segmented in molecular terms at the time of Hox activation. Conversely, the activation of a distinct Hox-code without a previous "molecular segmentation" may specify rhombomeres with their own boundaries. This would explain why RA expands but does not duplicate the postotic rhombomeres. Finally, the atavistic transformations obtained by overexpressing Hox genes in the wrong place suggest that evolution might be introducing modifications within Hox regulatory regions. Thus, changes in their expression domains could sustain phylogenetic requirements.
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Hox proteins have long been known to function as transcriptional regulators during development of the vertebrate hindbrain. In particular, these factors are thought to play key roles in assigning distinct fates to the rhombomere segments arising in the embryonic hindbrain. However, it remains uncertain exactly how the Hox proteins fit into the regulatory networks controlling hindbrain formation. For instance, it is unclear if Hox proteins fulfill similar roles in different rhombomeres and if they are absolutely required for all aspects of each rhombomere fate. Recent advances in the discovery, characterization and functional analysis of hindbrain gene regulatory networks is now allowing us to revisit these types of questions. In this review we focus on recent data on the formation of caudal rhombomeres in vertebrates, with a specific focus on zebrafish, to derive an up-to-date view of the role for Hox proteins in the regulation of hindbrain development.
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