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Control of retinoic acid synthesis and FGF expression in the nasal pit is required to pattern the craniofacial skeleton.

Endogenous retinoids are important for patterning many aspects of the embryo including the branchial arches and frontonasal region of the embryonic face. The nasal placodes express retinaldehyde dehydrogenase-3 (RALDH3) and thus retinoids from the placode are a potential patterning influence on the developing face. We have carried out experiments that have used Citral, a RALDH antagonist, to address the function of retinoid signaling from the nasal pit in a whole embryo model. When Citral-soaked beads were implanted into the nasal pit of stage 20 chicken embryos, the result was a specific loss of derivatives from the lateral nasal prominences. Providing exogenous retinoic acid residue development of the beak demonstrating that most Citral-induced defects were produced by the specific blocking of RA synthesis. The mechanism of Citral effects was a specific increase in programmed cell death on the lateral (lateral nasal prominence) but not the medial side (frontonasal mass) of the nasal pit. Gene expression studies were focused on the Bone Morphogenetic Protein (BMP) pathway, which has a well-established role in programmed cell death. Unexpectedly, blocking RA synthesis decreased rather than increased Msx1, Msx2, and Bmp4 expression. We also examined cell survival genes, the most relevant of which was Fgf8, which is expressed around the nasal pit and in the frontonasal mass. We found that Fgf8 was not initially expressed along the lateral side of the nasal pit at the start of our experiments, whereas it was expressed on the medial side. Citral prevented upregulation of Fgf8 along the lateral edge and this may have contributed to the specific increase in programmed cell death in the lateral nasal prominence. Consistent with this idea, exogenous FGF8 was able to prevent cell death, rescue most of the morphological defects and was able to prevent a decrease in retinoic acid receptorbeta (Rarbeta) expression caused by Citral. Together, our results demonstrate that endogenous retinoids act upstream of FGF8 and the balance of these two factors is critical for regulating programmed cell death and morphogenesis in the face. In addition, our data suggest a novel role for endogenous retinoids from the nasal pit in controlling the precise downregulation of FGF in the center of the frontonasal mass observed during normal vertebrate development.

Acyclic Monoterpenes↗

Dorsal patterning defects in the hindbrain, roof plate and skeleton in the dreher (dr(J)) mouse mutant.

dreher is a spontaneous mouse mutation in which adult animals display a complex phenotype associated with hearing loss, neurological, pigmentation and skeletal abnormalities. During early embryogenesis, the neural tube of dreher mutants is abnormally shaped in the region of the rhomboencephalon, due to problems in the formation of a proper roof plate over the otic hindbrain. We have studied the expression of Hox/lacZ transgenic mouse strains in the dreher background and shown that primary segmentation of the neural tube is not altered in these mutants, although correct morphogenesis is affected resulting in misshapen rhombomeres. Neural crest derivatives from rhombomere 6, such as the glossopharyngeal ganglion, are defective, and the dorsal neural tube marker Wnt1 is absent from this segment. Selected trunk neural crest populations are also altered, as there is a lack of pigmentation in the thoracic region of mutant mice. Skeletal defects include abnormal cranial bones of neural crest origin, and improper fusion of the dorsal aspects of cervical and thoracic vertebrae. Taken together, the gene affected in the dreher mutant is responsible for correct patterning of the dorsal-most cell types of the neural tube, that is, the neural crest and the roof plate, in the hindbrain region. Axial skeletal defects could reflect inductive influence of the dorsal neural tube on proper fusion of the neural arches. It is possible that a common precursor population for both neural crest and roof plate is the cellular target of the dreher mutation.

Animals↗

Bapx1: an evolutionary conserved homologue of the Drosophila bagpipe homeobox gene is expressed in splanchnic mesoderm and the embryonic skeleton.

In Drosophila, the visceral mesoderm giving rise to gut musculature is specified by the bagpipe homeobox gene. We have isolated, from both mouse and human, homologues of the bagpipe gene designated Bapx1 and BAPX1, respectively. Bapx1 encodes a predicted protein of 333 amino acids, and has significant regions of homology outside the homeodomain with members of the NK homeobox gene superfamily. Bapx1 maps to the proximal end of chromosome 5 in mouse, near the Msx1 gene. The syntenic region in human corresponds to a chromosomal region containing loci for several skeletal disorders. Bapx1 is first detectable in embryos just prior to axis rotation in lateral plate mesoderm (splanchnic mesoderm) adjacent to the endodermal lining of the prospective gut, and in the most newly formed somites in the region corresponding to the presclerotome, the precursor of the vertebrae. Thus, Bapx1 is one of the earliest developmental markers for the sclerotome portion of the somite and the gut mesentery. Bapx1 continues to be expressed well into organogenesis in lateral plate mesoderm surrounding the mid- and hindgut, and in essentially all cartilaginous condensations which will subsequently undergo endochondral bone formation. The expression pattern of Bapx1 in murine embryos suggests that there are evolutionary conserved mechanisms of visceral mesoderm development across the animal kingdom, and that the mammalian Bapx1 gene may have recently acquired an additional developmental role in skeletal patterning.

Amino Acid Sequence↗

Skeleton keys.

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Americas↗

The axial skeleton of the Devonian tetrapod Ichthyostega.

Ichthyostega was the first Devonian tetrapod to be subject to a whole-body reconstruction. It remains, together with Acanthostega, one of only two Devonian tetrapods for which near-complete postcranial material is available. It is thus crucially important for our understanding of the earliest stages of tetrapod evolution and terrestrialization. Here we show a new reconstruction of Ichthyostega based on extensive re-examination of original material and augmented by recently collected specimens. Our reconstruction differs substantially from those previously published and reveals hitherto unrecognized regionalization in the vertebral column. Ichthyostega is the earliest vertebrate to show obvious adaptations for non-swimming locomotion. Uniquely among early tetrapods, the presacral vertebral column shows pronounced regionalization of neural arch morphology, suggesting that it was adapted for dorsoventral rather than lateral flexion.

Amphibians↗