Biomedical subjects

Isabelle Miletich

Publications and source records attributed to Isabelle Miletich.

8 recordsLinked to original sources

PubMed2006

Satb2 haploinsufficiency phenocopies 2q32-q33 deletions, whereas loss suggests a fundamental role in the coordination of jaw development.

The recent identification of SATB2 as a candidate gene responsible for the craniofacial dysmorphologies associated with deletions and translocations at 2q32-q33, one of only three regions of the genome for which haploinsufficiency has been significantly associated with isolated cleft palate, led us to investigate the in vivo functions of murine Satb2. We find that, similar to the way in which SATB2 is perceived to act in humans, craniofacial defects due to haploinsufficiency of Satb2, including cleft palate (in approximately 25% of cases), phenocopy those seen with 2q32-q33 deletions and translocations in humans. Full functional loss of Satb2 results in amplification of these defects and leads both to increased apoptosis in the craniofacial mesenchyme where Satb2 is usually expressed and to changes in the pattern of expression of three genes implicated in the regulation of craniofacial development in humans and mice: Pax9, Alx4, and Msx1. The Satb2-dosage sensitivity in craniofacial development is conspicuous--along with its control of cell survival, pattern of expression, and reversible functional modification by SUMOylation, it suggests that Satb2/SATB2 function in craniofacial development may prove to be more profound than has been anticipated previously. Because jaw development is Satb2-dosage sensitive, the regulators of Satb2 expression and posttranslational modification become of critical importance both ontogenetically and evolutionarily, especially since such regulators plausibly play undetected roles in jaw and palate development and in the etiology of craniofacial malformations.

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PubMed2005

Expression of the Hedgehog antagonists Rab23 and Slimb/betaTrCP during mouse tooth development.

The sonic hedgehog signalling peptide has been demonstrated to play an important role in the growth and patterning of several organs including the tooth. Inappropriate activation of Shh signalling in the embryo causes various patterning defects and complex regulation of this pathway is important during normal development. A growing list of diverse antagonists have been identified that restrict Shh signalling in the embryo, however, only Ptc1, Gas1 and Hip1 have been studied during tooth development. We have examined the expression pattern of the putative antagonists Rab23 and Slimb/betaTrCP during early murine odontogenesis and find that these molecules are expressed in the developing tooth. Interestingly, Rab23 demonstrates contrasting expression domains in the incisor and molar dentition during the cap stage, being restricted to the mesenchymal compartment of molar teeth and the epithelium of the enamel knot in incisor teeth. These findings provide the first evidence of distinct regulatory pathways for Shh in teeth of different classes.

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PubMed2005

The stomach mesenchymal transcription factor Barx1 specifies gastric epithelial identity through inhibition of transient Wnt signaling.

Inductive interactions between gut endoderm and the underlying mesenchyme pattern the developing digestive tract into regions with specific morphology and functions. The molecular mechanisms behind these interactions are largely unknown. Expression of the conserved homeobox gene Barx1 is restricted to the stomach mesenchyme during gut organogenesis. Using recombinant tissue cultures, we show that Barx1 loss in the mesenchyme prevents stomach epithelial differentiation of overlying endoderm and induces intestine-specific genes instead. Additionally, Barx1 null mouse embryos show visceral homeosis, with intestinal gene expression within a highly disorganized gastric epithelium. Barx1 directs mesenchymal cell expression of two secreted Wnt antagonists, sFRP1 and sFRP2, and these factors are sufficient replacements for Barx1 function. Canonical Wnt signaling is prominent in the prospective gastric endoderm prior to epithelial differentiation, and its inhibition by Barx1-dependent signaling permits development of stomach-specific epithelium. These results define a transcriptional and signaling pathway of inductive cell interactions in vertebrate organogenesis.

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PubMed2005

Barx1 and evolutionary changes in feeding.

During mouse embryonic development, the Barx1 homeobox gene is expressed in the mesenchymal cells of molar teeth and stomach. During early stages of molar development, Barx1 has an instructive role, directing the as yet undetermined ectomesenchymal cells in the proximal region of the jaws to follow a multicuspid tooth developmental pathway. We review here recent results showing an absence of stomach tissue in Barx1 mutant mice. The data strongly suggest that in the presumptive stomach mesenchyme Barx1 acts to attenuate Wnt signalling allowing digestive tract endoderm to differentiate into a highly specialized stomach epithelium. In the light of these new data, we discuss the possibility that evolutionary changes in the Barx1 gene could have simultaneously altered the dentition and the digestive system, therefore positioning Barx1 as a key gene in the evolution of mammals.

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PubMed2004

Restriction of sonic hedgehog signalling during early tooth development.

The signalling peptide encoded by the sonic hedgehog gene is restricted to localised thickenings of oral epithelium, which mark the first morphological evidence of tooth development, and is known to play a crucial role during the initiation of odontogenesis. We show that at these stages in the murine mandibular arch in the absence of epithelium, the Shh targets Ptc1 and Gli1 are upregulated in diastema mesenchyme, an edentulous region between the sites of molar and incisor tooth formation. This ectopic expression is not associated with Shh transcription but with Shh protein, undetectable in the presence of epithelium. These findings suggest that, in diastema mesenchyme, restriction of Shh activity is dependent upon the overlying epithelium. This inhibitory activity was demonstrated by the ability of transplanted diastema epithelium to downregulate Ptc1 in tooth explants, and for isolated diastema mesenchyme to express Ptc1. A candidate inhibitor in diastema mesenchyme is the glycosylphosphatidylinositol-linked membrane glycoprotein Gas1. Gas1 is normally expressed throughout mandibular arch mesenchyme; however, in the absence of epithelium this expression was downregulated specifically in the diastema where ectopic Shh protein was identified. Although Shh signalling has no effect upon Gas1 expression in mandibular arch mesenchyme, overexpression of Gas1 results in downregulation of ectopic Ptc1. Therefore, control of the position of tooth initiation in the mandibular arch involves a combination of Shh signalling at sites where teeth are required and antagonism in regions destined to remain edentulous.

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PubMed2004

Neural crest contribution to mammalian tooth formation.

The cranial neural crest cells, which are specialized cells of neural origin, are central to the process of mammalian tooth development. They are the only source of mesenchyme able to sustain tooth development, and give rise not only to most of the dental tissues, but also to the periodontium, the surrounding tissues that hold teeth in position. Tooth organogenesis is regulated by a series of interactions between cranial neural crest cells and the oral epithelium. In the development of a tooth, the epithelium covering the inside of the developing oral cavity provides the first instructive signals. Signaling molecules secreted by the oral epithelium 1) establish large cellular fields competent to form a specific tooth shape (mono- or multicuspid) along a proximodistal axis; 2) define an oral (capable of forming teeth) and non-oral mesenchyme along a rostrocaudal axis; and 3) position the sites of future tooth development. The critical information to model tooth shape resides later in the neural crest-derived mesenchyme. Cranial neural crest cells ultimately differentiate into highly specialized cell types to produce mature dental organs. Some cranial neural crest cells located in the dental pulp, however, maintain plasticity in their developmental potential up to postnatal life, offering new prospects for regeneration of dental tissues.

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PubMed2003

Directed expression of the HIV-1 accessory protein Vpu in Drosophila fat-body cells inhibits Toll-dependent immune responses.

Human immunodeficiency virus 1 (HIV-1) expresses several accessory proteins that manipulate various host-cell processes to achieve optimum replicative efficiency. One of them, viral protein U (Vpu), has been shown to interfere with the cellular degradation machinery through interaction with SCF(beta-TrCP) complexes. To learn more about Vpu function in vivo, we used the genetically tractable fruit fly, Drosophila melanogaster. Our results show that the directed expression of Vpu, but not the non-phosphorylated form, Vpu2/6, in fat-body cells affects Drosophila antimicrobial responses. In flies, the Toll and Imd pathways regulate antimicrobial-peptide gene expression. We show that Vpu specifically affects Toll pathway activation by inhibiting Cactus degradation. Given the conservation of the Toll/nuclear factor-kappa B (NF-kappa B) signalling pathways between flies and mammals, our results suggest a function for Vpu in the inhibition of host NF-kappa B-mediated innate immune defences and provide a powerful genetic approach for studying Vpu inhibition of NF-kappa B signalling in vivo.

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PubMed2003

Normal and abnormal dental development.

Teeth are vertebrate organs that arise from complex and progressive interactions between an ectoderm, the oral epithelium and an underlying mesenchyme. During their early development, tooth germs exhibit many morphological and molecular similarities with other developing epithelial appendages, such as hair follicles, mammary and salivary glands, lungs, kidneys, etc. The developing mouse tooth germ, which is an experimentally accessible model for organogenesis, provides a powerful tool for elucidating the molecular mechanisms that control the development of these organs. Dentition patterning also provides a unique model for understanding how different shapes of teeth arise in different regions of the jaws. We review here the main signalling networks mediating the epithelial-mesenchymal interactions involved in tooth morphogenesis and patterning.

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