Biomedical subjects

Jennifer Selever

Publications and source records attributed to Jennifer Selever.

5 recordsLinked to original sources

PubMed2006

BMP receptor type IA in limb bud mesenchyme regulates distal outgrowth and patterning.

The mesenchyme of the developing vertebrate limb responds to inductive signals, giving rise to skeletal elements that define limb shape and size. Several signals emanate from the limb ectoderm and in particular from the specialized epithelium of the apical ectodermal ridge (AER), including three members of the bone morphogenetic protein (BMP) family of signaling molecules, BMP2, BMP4 and BMP7. Using the Cre/loxP system in mice, we rendered limb bud mesenchyme insensitive to BMP signals through the type I receptor, BMPR-IA. Conditional mutants had shortened limbs and almost complete agenesis of the autopod because of reduced cell proliferation. Reduced expression of downstream BMP signaling targets, Msx1, Msx2 and gremlin in the distal mesenchyme (progress zone) correlated with decreased levels of cyclin D1 and Wnt5a. Ectopic anterior activation of sonic hedgehog (SHH) signaling and Hox expression revealed alterations in anterior-posterior (AP) patterning. Abnormal localization of Lmx1b-expressing cells in the ventral mesenchyme, along with histological alterations and an abnormal melanization pattern of the limb, indicate altered dorsal-ventral (DV) boundaries. These findings suggest that signaling through BMPR-IA in limb mesenchyme is essential for distal outgrowth and also influences AP and DV patterning.

Animals↗

PubMed2005

Threshold-specific requirements for Bmp4 in mandibular development.

Mandibular development is regulated by an interplay between a specified branchial arch ectoderm and a plastic mesenchyme. Moreover, signaling from the pharyngeal endoderm has been shown to be important for mandibular morphogenesis. To gain insight into the mechanisms regulating mandibular pattern, it is important to investigate the function of the epithelial-derived signals. Bmp4 is expressed in both distal, mandibular arch ectoderm and pharyngeal endoderm. Here, we show that deletion of Bmp4 in the mandibular ectoderm and to a lesser extent in the pharyngeal endoderm, resulted in severe defects in mandibular development. Furthermore, our data uncovered different Bmp4 thresholds for expression of the Bmp-dependent Msx1 and Msx2 genes in mandibular mesenchyme. We also found that ectodermal Fgf8 expression was both activated and repressed by Bmp4 in a dosage-dependent fashion indicating a novel Bmp4 function in threshold-specific regulation of Fgf8 transcription. Lastly, we provide evidence that Prx homeobox genes repress expression of an Msx2 transgene, previously shown to be Bmp4-responsive, revealing a mechanism for differential regulation of Msx1 and Msx2 by Bmp signaling.

Animals↗

PubMed2004

Bmp4 in limb bud mesoderm regulates digit pattern by controlling AER development.

In the developing limb, Bmp4 is expressed in the apical ectodermal ridge (AER) and underlying mesoderm. Insight into the function of Bmp4 in limb development has been hampered by the early embryonic lethality of Bmp4 null embryos. We directly investigated Bmp4 using a conditional null allele of Bmp4 and the Prx1(cre) transgene to inactivate Bmp4 in limb bud mesoderm. The limb bud mesoderm of Prx1(cre);Bmp4 mutants was defective in production of Bmp4 but still competent to respond to Bmp signaling. Prx1(cre);Bmp4 mutant embryos had defective digit patterning including hindlimb preaxial polydactyly with posterior digit transformations. The Prx1(cre);Bmp4 mutants also had postaxial polydactyly with digit five duplications. Bmp4 mutant limbs had delayed induction and maturation of the AER that resulted in expanded Shh signaling. Moreover, the AER persisted longer in the Bmp4 mutant limb buds exposing the forming digits to prolonged Fgf8 signaling. Our data show that Bmp4 in limb mesoderm regulates AER induction and maturation and implicate signaling from the AER in regulation of digit number and identity.

Animals↗

PubMed2004

Bmp4 signaling is required for outflow-tract septation and branchial-arch artery remodeling.

The Bmp4 signaling molecule is expressed in ventral splanchnic and branchial-arch mesoderm and outflow-tract (OFT) myocardium, suggesting a role for Bmp4 in OFT development. Inactivation of Bmp4 in the caudal branchial arch and splanchnic mesoderm and OFT myocardium by using a conditional null allele of Bmp4 and the Nkx2.5cre recombinase allele resulted in abnormal morphogenesis of branchial-arch arteries (BAAs) and defective OFT septation. Expression of aortic-sac myocardial markers was reduced and expression of the sm22LacZ transgene, a smooth-muscle marker, was attenuated in BAAs and conotruncus of Nkx2.5cre; Bmp4 conditional mutants. Moreover, we found tissue-specific functions for Bmp4 in the regulation of cellular proliferation and apoptosis. We also demonstrate a strong genetic interaction between Bmp4 and Bmp7 in OFT development. Our findings uncover a previously uncharacterized function for Bmp4 in vascular remodeling of the BAAs, and they show definitively that Bmp4, in cooperation with Bmp7, has a central role in OFT septation.

Animals↗

PubMed2003

Genetic dissection of Pitx2 in craniofacial development uncovers new functions in branchial arch morphogenesis, late aspects of tooth morphogenesis and cell migration.

Pitx2, a paired-related homeobox gene that encodes multiple isoforms, is the gene mutated in the haploinsufficient Rieger Syndrome type 1 that includes dental, ocular and abdominal wall anomalies as cardinal features. Previous analysis of the craniofacial phenotype of Pitx2-null mice revealed that Pitx2 was both a positive regulator of Fgf8 and a repressor of Bmp4-signaling, suggesting that Pitx2 may function as a coordinator of craniofacial signaling pathways. We show that Pitx2 isoforms have interchangeable functions in branchial arches and that Pitx2 target pathways respond to small changes in total Pitx2 dose. Analysis of Pitx2 allelic combinations that encode varying levels of Pitx2 showed that repression of Bmp signaling requires high Pitx2 while maintenance of Fgf8 signaling requires only low Pitx2. Fate-mapping studies with a Pitx2 cre recombinase knock in allele revealed that Pitx2 daughter cells are migratory and move aberrantly in the craniofacial region of Pitx2 mutant embryos. Our data reveal that Pitx2 function depends on total Pitx2 dose and rule out the possibility that the differential sensitivity of target pathways was a consequence of isoform target specificity. Moreover, our results uncover a new function of Pitx2 in regulation of cell motility in craniofacial development.

Abnormalities, Multiple↗