As classically described, the precardiac mesoderm of the paired heart-forming fields migrate and fuse anteriomedially in the ventral midline to form the first segment of the straight heart tube. This segment ultimately forms the right trabeculated ventricle. Additional segments are added to the caudal end of the first in a sequential fashion from the posteriolateral heart-forming field mesoderm. In this study we report that the final major heart segment, which forms the cardiac outflow tract, does not follow this pattern of embryonic development. The cardiac outlet, consisting of the conus and truncus, does not derive from the paired heart-forming fields, but originates separately from a previously unrecognized source of mesoderm located anterior to the initial primitive heart tube segment. Fate-mapping results show that cells labeled in the mesoderm surrounding the aortic sac and anterior to the primitive right ventricle are incorporated into both the conus and the truncus. Conversely, if cells are labeled in the existing right ventricle no incorporation into the cardiac outlet is observed. Tissue explants microdissected from this anterior mesoderm region are capable of forming beating cardiac muscle in vitro when cocultured with explants of the primitive right ventricle. These findings establish the presence of another heart-forming field. This anterior heart-forming field (AHF) consists of mesoderm surrounding the aortic sac immediately anterior to the existing heart tube. This new concept of the heart outlet's embryonic origin provides a new basis for explaining a variety of gene-expression patterns and cardiac defects described in both transgenic animals and human congenital heart disease.
Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.
Abstract-Lipoma preferred partner (LPP) is a proline rich LIM domain family protein highly expressed at plasma membrane dense bodies and focal adhesions in smooth muscle cells. 1 Using the C-terminus of LPP as bait in a yeast two hybrid system, palladin, an actin-associated protein was identified. The palladin interacting region of LPP was mapped to the first and second LIM domains. The N-terminus of palladin interacted with LPP both in vitro and in vivo, but not solely through its FPLPPP and FPPPP motifs. Like LPP, palladin, is highly expressed in differentiated smooth muscle, colocalized at focal adhesions, at isolated lamellipodia and at dense bodies in smooth muscle tissue. Both LPP and palladin enhanced cell migration and spreading. LPP and palladin expression was markedly decreased, in contrast to vinculin or paxillin, in migration defective focal adhesion kinase null cells Key Words: lipoma preferred partner Ⅲ migration Ⅲ palladin Ⅲ smooth muscle Ⅲ vascular injury V ascular smooth muscle cells (SMCs) are not terminally differentiated and have the ability to undergo phenotypic modulation. For example, SMCs are highly migratory during vasculogenesis, under go extensive rates of proliferation in response to vascular injury and can increase contractile protein mass in response to hypertrophic stimuli. Cell migration is a dynamic and integrated process, requiring the participation of specialized cell surface receptors at focal adhesions, structural proteins, signaling and cytoskeletal proteins which have scaffold and regulatory roles. Lipoma preferred partner (LPP), is a focal adhesion protein which has proline rich domains and LIM domains. 3 LIM domains often mediate the assembly of multiprotein complexes that regulate cell motility and gene transcription. Through it's three LIM domains LPP may function as an adaptor protein to anchor structural or regulatory proteins to focal adhesions and plasmalemmal dense bodies in SMCs and tissues respectively. 1,4 Using tissue screens and oligonucleotide microarray transcriptional profiling, LPP has been shown to be a smooth muscle (SM) restricted protein in vivo. 1,5 Based on the recognized role of LIM domains in the assembly of multiprotein complexes at focal adhesions, a yeast two hybrid screen was used to isolate LPP partners, identifying palladin, a protein most highly but not exclusively expressed in SM. To better understand the function and regulation of LPP and palladin in vascular SMC during phenotypic modulation, we have investigated the regulation of their expression as well as their role in SMC migration. Overexpression or downregulation of LPP results in an increase or decrease respectively in cell migration. 1,2 SM ␣-actin (SMA) and SM myosin heavy chain (MHC), expression are down regulated by alterations in the actin cytoskeleton through inhibition of the RhoA/ROCK signaling pathway. 6 LPP expression is also downregulated by C3 or ROCK inhibition. 2 Therefore we determined whether expression of these focal adhesion proteins as with the cytoskeletal prot...
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