Mouth development

WIREs Developmental Biology published by Wiley Periodicals, Inc. A mouth is present in all animals, and comprises an opening from the outside into the oral cavity and the beginnings of the digestive tract to allow eating. This review focuses on the earliest steps in mouth formation. In the first half, we conclude that the mouth arose once during evolution. In all animals, the mouth forms from ectoderm and endoderm. A direct association of oral ectoderm and digestive endoderm is present even in triploblastic animals, and in chordates, this region is known as the extreme anterior domain (EAD). Further support for a single origin of the mouth is a conserved set of genes that form a ‘mouth gene program’ including foxA and otx2. In the second half of this review, we discuss steps involved in vertebrate mouth formation, using the frog Xenopus as a model. The vertebrate mouth derives from oral ectoderm from the anterior neural ridge, pharyngeal endoderm and cranial neural crest (NC). Vertebrates form a mouth by breaking through the body covering in a precise sequence including specification of EAD ectoderm and endoderm as well as NC, formation of a ‘pre-mouth array,’ basement membrane dissolution, stomodeum formation, and buccopharyngeal membrane perforation. In Xenopus, the EAD is also a craniofacial organizer that guides NC, while reciprocally, the NC signals to the EAD to elicit its morphogenesis into a pre-mouth array. Human mouth anomalies are prevalent and are affected by genetic and environmental factors, with understanding guided in part by use of animal models.National Institute of Dental and Craniofacial Research (U.S.) (Grant RO1 DE021109

Zebrafish con/disp1 reveals multiple spatiotemporal requirements for Hedgehog-signaling in craniofacial development

<p>Abstract</p> <p>Background</p> <p>The vertebrate head skeleton is derived largely from cranial neural crest cells (CNCC). Genetic studies in zebrafish and mice have established that the Hedgehog (Hh)-signaling pathway plays a critical role in craniofacial development, partly due to the pathway's role in CNCC development. Disruption of the Hh-signaling pathway in humans can lead to the spectral disorder of Holoprosencephaly (HPE), which is often characterized by a variety of craniofacial defects including midline facial clefting and cyclopia <abbrgrp><abbr bid="B1">1</abbr><abbr bid="B2">2</abbr></abbrgrp>. Previous work has uncovered a role for Hh-signaling in zebrafish dorsal neurocranium patterning and chondrogenesis, however Hh-signaling mutants have not been described with respect to the ventral pharyngeal arch (PA) skeleton. Lipid-modified Hh-ligands require the transmembrane-spanning receptor Dispatched 1 (Disp1) for proper secretion from Hh-synthesizing cells to the extracellular field where they act on target cells. Here we study <it>chameleon </it>mutants, lacking a functional <it>disp1</it>(<it>con/disp1</it>).</p> <p>Results</p> <p><it>con/disp1 </it>mutants display reduced and dysmorphic mandibular and hyoid arch cartilages and lack all ceratobranchial cartilage elements. CNCC specification and migration into the PA primorida occurs normally in <it>con/disp1 </it>mutants, however <it>disp1 </it>is necessary for post-migratory CNCC patterning and differentiation. We show that <it>disp1 </it>is required for post-migratory CNCC to become properly patterned within the first arch, while the gene is dispensable for CNCC condensation and patterning in more posterior arches. Upon residing in well-formed pharyngeal epithelium, neural crest condensations in the posterior PA fail to maintain expression of two transcription factors essential for chondrogenesis, <it>sox9a </it>and <it>dlx2a</it>, yet continue to robustly express other neural crest markers. Histology reveals that posterior arch residing-CNCC differentiate into fibrous-connective tissue, rather than becoming chondrocytes. Treatments with Cyclopamine, to inhibit Hh-signaling at different developmental stages, show that Hh-signaling is required during gastrulation for normal patterning of CNCC in the first PA, and then during the late pharyngula stage, to promote CNCC chondrogenesis within the posterior arches. Further, loss of <it>disp1 </it>disrupted normal expression of <it>bapx1 </it>and <it>gdf5</it>, markers of jaw joint patterning, thus resulting in jaw joint defects in <it>con/disp1 </it>mutant animals.</p> <p>Conclusion</p> <p>This study reveals novel requirements for Hh-signaling in the zebrafish PA skeleton and highlights the functional diversity and differential sensitivity of craniofacial tissues to Hh-signaling throughout the face, a finding that may help to explain the spectrum of human facial phenotypes characteristic of HPE.</p

Vers un nouveau mode d'exercice de la pharmacie (la loi sur les nouvelles régulations économiques et la loi MURCEF)

PARIS-BIUP (751062107) / SudocSudocFranceF

Etude embryologique et génétique du développement des structures nasales des vertébrés (perspectives évolutives et applications cliniques)

L organe nasal des animaux est un complexe anatomique ancien comportant récepteurs sensoriels, nerfs et bulbes olfactifs. Chez les vertébrés, il est protégé par une capsule cartilagineuse, paire et symétrique de grande variabilité anatomique. Cette capsule comporte une partie inférieure, le mésethmoïde et une partie supérieure, l ectethmoïde, protégeant l organe olfactif. Chaque partie provient des cellules de la crête neurale céphalique homolatérales recevant des signaux moléculaires d origines différentes. Nos travaux expérimentaux déterminent la double origine de la capsule nasale. Nous avons démontré que la morphogénèse du mésethmoïde dépend de la signalisation Sonic hedgehog délivré par l endoderme rostral embryonnaire ; et que celle de l ectethmoïde dépend de signaux provenant du bourrelet neural antérieur exprimant Dlx5 et Dlx6. Nous proposons une nouvelle classification des malformations naso-frontales humaines permettant de formuler un pronostic intellectuel.The animal nasal organ is an old anatomical complex including sensory receptors, nerves and olfactory bulbs. In vertebrates, it is protected by a cartilaginous capsule, a pair and symmetric structure displaying extensive anatomical diversity. It is build by a lower part, the mesethmoïd; and an upper part, the ectethmoïd protecting the olfactory organ. Each part is generated by the ipsilateral cranial neural crest cells, which receive molecular signals of different origins. Our work leads us to determine the double origin of the nasal capsule. We have shown that mesethmoïd morphogenesis depends upon Sonic hedgehog signalling from the rostral embryonic endoderm, while the formation of the ectethmoïd depends upon signals from the anterior neural ridge expressing Dlx5 and Dlx6. We propose a new classification of nasofrontal malformations in human, useful to formulate an intellectual prognosis.PARIS-Museum Hist.Naturelle (751052304) / SudocSudocFranceF

Sonic hedgehog signalling from foregut endoderm patterns the avian nasal capsule

International audienc

Dlx5 and Dlx6 expression in the anterior neural fold is essential for patterning the dorsal nasal capsule

International audienc

Tumor Necrosis Factor-Alpha-Elicited Stimulation of Gamma-Secretase Is Mediated by C-Jun N-Terminal Kinase-Dependent Phosphorylation of Presenilin and Nicastrin

gamma-Secretase is a multiprotein complex composed of presenilin (PS), nicastrin (NCT), Aph-1, and Pen-2, and it catalyzes the final proteolytic step in the processing of amyloid precursor protein to generate amyloid- beta. Our previous results showed that tumor necrosis factor-alpha ( TNF- alpha) can potently stimulate gamma-secretase activity through a c-Jun N- terminal kinase (JNK)-dependent pathway. Here, we demonstrate that TNF- alpha triggers JNK-dependent serine/threonine phosphorylation of PS1 and NCT to stimulate gamma-secretase activity. Blocking of JNK activity with a potent JNK inhibitor (SP600125) reduces TNF-alpha-triggered phosphorylation of PS1 and NCT. Consistent with this, we show that activated JNKs can be copurified with gamma- secretase complexes and that active recombinant JNK2 can promote the phosphorylation of PS1 and NCT in vitro. Using site-directed mutagenesis and a synthetic peptide, we clearly show that the Ser(319)Thr(320) motif in PS1 is an important JNK phosphorylation site that is critical for the TNF-alpha-elicited regulation of gamma-secretase. This JNK phosphorylation of PS1 at Ser(319) Thr(320) enhances the stability of the PS1 C-terminal fragment that is necessary for gamma-secretase activity. Together, our findings strongly suggest that JNK is a critical intracellular mediator of TNF-alpha- elicited regulation of gamma-secretase and governs the pivotal step in the assembly of functional gamma-secretase