Biomedical subjects

Mei-Fang Lu

Publications and source records attributed to Mei-Fang Lu.

6 recordsLinked to original sources

PubMed2006

Pitx2 promotes development of splanchnic mesoderm-derived branchiomeric muscle.

Recent experiments, showing that both cranial paraxial and splanchnic mesoderm contribute to branchiomeric muscle and cardiac outflow tract (OFT) myocardium, revealed unexpected complexity in development of these muscle groups. The Pitx2 homeobox gene functions in both cranial paraxial mesoderm, to regulate eye muscle, and in splanchnic mesoderm to regulate OFT development. Here, we investigated Pitx2 in branchiomeric muscle. Pitx2 was expressed in branchial arch core mesoderm and both Pitx2 null and Pitx2 hypomorphic embryos had defective branchiomeric muscle. Lineage tracing with a Pitx2cre allele indicated that Pitx2 mutant descendents moved into the first branchial arch. However, markers of both undifferentiated core mesoderm and specified branchiomeric muscle were absent. Moreover, lineage tracing with a Myf5cre allele indicated that branchiomeric muscle specification and differentiation were defective in Pitx2 mutants. Conditional inactivation in mice and manipulation of Pitx2 expression in chick mandible cultures revealed an autonomous function in expansion and survival of branchial arch mesoderm.

Animals↗

PubMed2006

Pitx2 regulates cardiac left-right asymmetry by patterning second cardiac lineage-derived myocardium.

Current models of left-right asymmetry hold that an early asymmetric signal is generated at the node and transduced to lateral plate mesoderm in a linear signal transduction cascade through the function of the Nodal signaling molecule. The Pitx2 homeobox gene functions at the final stages of this cascade to direct asymmetric morphogenesis of selected organs including the heart. We previously showed that Pitx2 regulated an asymmetric pathway that was independent of cardiac looping suggesting a second asymmetric cardiac pathway. It has been proposed that in the cardiac outflow tract Pitx2 functions in both cardiac neural crest, as a target of canonical Wnt-signaling, and in the mesoderm-derived cardiac second lineage. We used fate mapping, conditional loss of function, and chimera analysis in mice to investigate the role of Pitx2 in outflow tract morphogenesis. Our findings reveal that Pitx2 is dispensable in the cardiac neural crest but functions in second lineage myocardium revealing that this cardiac progenitor field is patterned asymmetrically.

Animals↗

PubMed2005

Bmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterning.

Cardiac cushion development provides a valuable system to investigate epithelial to mesenchymal transition (EMT), a fundamental process in development and tumor progression. In the atrioventricular (AV) canal, endocardial cells lining the heart respond to a myocardial-derived signal, undergo EMT, and contribute to cushion mesenchyme. Here, we inactivated bone morphogenetic protein 2 (Bmp2) in the AV myocardium of mice. We show that Bmp2 has three functions in the AV canal: to enhance formation of the cardiac jelly, to induce endocardial EMT and to pattern the AV myocardium. Bmp2 is required for myocardial expression of Has2, a crucial component of the cardiac jelly matrix. During EMT, Bmp2 promotes expression of the basic helix-loop-helix factor Twist1, previously implicated in EMT in cancer metastases, and the homeobox genes Msx1 and Msx2. Deletion of the Bmp type 1A receptor, Bmpr1a, in endocardium also resulted in failed cushion formation, indicating that Bmp2 signals directly to cushion-forming endocardium to induce EMT. Lastly, we show that Bmp2 mutants failed to specify the AV myocardium with loss of Tbx2 expression uncovering a myocardial, planar signaling function for Bmp2. Our data indicate that Bmp2 has a crucial role in coordinating multiple aspects of AV canal morphogenesis.

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↗