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Publications (84)
The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as a key regulator of inflammation. Initially, uPA/uPAR was considered thrombolytic (clot-dissolving); however, recent studies have demonstrated its predominant immunomodulatory functions in inflammation and cancer. The uPA/uPAR complex ha...
Efficient repair of skeletal muscle relies upon the precise coordination of cells between the satellite cell niche and innate immune cells that are recruited to the site of injury. The expression of pro-inflammatory cytokines and chemokines such as TNFα, IFNγ, CXCL1, and CCL2, by muscle and tissue resident immune cells recruits neutrophils and M1 m...
Muscular dystrophies are a heterogeneous group of genetic muscle-wasting disorders that are subdivided based on the region of the body impacted by muscle weakness as well as the functional activity of the underlying genetic mutations. A common feature of the pathophysiology of muscular dystrophies is chronic inflammation associated with the replace...
Background: The expression of proinflammatory signals at the site of muscle injury are essential for efficient tissue repair and their dysregulation can lead to inflammatory myopathies. Macrophages, neutrophils, and fibroadipogenic progenitor cells residing in the muscle are significant sources of proinflammatory cytokines and chemokines. However,...
Duchenne muscular dystrophy is an X-linked disease afflicting 1 in 3500 males that is characterized by muscle weakness and wasting during early childhood, and loss of ambulation and death by early adulthood. Chronic inflammation due to myofiber instability leads to fibrosis, which is a primary cause of loss of ambulation and cardiorespiratory insuf...
Abstract Reptiles are the only amniotes that maintain the capacity to regenerate appendages. This study presents the first anatomical and histological evidence of tail repair with regrowth in an archosaur, the American alligator. The regrown alligator tails constituted approximately 6–18% of the total body length and were morphologically distinct f...
Reptiles are the only amniotes that maintain the capacity to lose and regrow entire appendages. Among reptiles, tail regeneration has been extensively studied in Lepidosauria, the subclass that includes lizards, but this study presents the first anatomical and histological evidence of tail regeneration in an archosaur, the American alligator ( Alli...
Duchenne muscular dystrophy (DMD) is a lethal, X-linked disease characterized by progressive muscle degeneration. The condition is driven by nonsense and missense mutations in the dystrophin gene, leading to instability of the sarcolemma and skeletal muscle necrosis and atrophy. Resulting changes in muscle-specific gene expression that take place i...
Injectable hydrogels provide a powerful and non-invasive approach for numerous applications in cell transplantation, growth factor delivery, tissue regeneration and so forth. The properties of injectable hydrogels should be well-tuned for specific applications, where their overall design should ensure biocompatibility, non-toxicity, robust mechanic...
Development of an ex vivo culture system to expand satellite cells, the resident muscle stem cell population, will be necessary for the development of their use as therapeutics. The loss of the niche environment is often cited as the reason that culture results in both the loss of myogenic potential and low re-engraftment rates of these cells. Stud...
Background
Duchenne muscular dystrophy (DMD) is a lethal, X-linked disease characterized by progressive muscle degeneration. The condition is driven by nonsense and missense mutations in the dystrophin gene, but the resulting changes in muscle-specific gene expression that take place in dystrophin’s absence remain uncharacterized, as they are poten...
The vertebral column is composed of alternating vertebrae and intervertebral discs and is supported by spinal ligaments and muscles. All of these components are essential to the structural integrity of the spine, which plays a vital role in protecting the spinal cord, transmitting the weight of the body, and providing a flexible axis for head and t...
Squamates include all lizards and snakes, and display some of the most diverse and extreme morphological adaptations among vertebrates. However, compared to birds and mammals, relatively few resources exist for comparative genomic analyses of squamates, hampering efforts to understand the molecular bases of phenotypic diversification in such a spec...
The lizards are evolutionarily the closest vertebrates to humans that demonstrate the ability to regenerate entire appendages containing cartilage, muscle, skin, and nervous tissue. We previously isolated PAX7-positive cells from muscle of the green anole lizard, Anolis carolinensis, that can differentiate into multinucleated myotubes and express t...
Humans and other vertebrates have evolved a robust repair mechanism required to respond to overuse, trauma, and disease. In amphibians, some reptiles and fish, entire muscles can be regenerated in response to amputation. Understanding the underlying mechanisms that control these processes has therapeutic implications for individuals where the sever...
MicroRNAs (miRNAs) regulate gene output by targeting degenerate elements in mRNAs and have undergone drastic expansions in higher metazoan genomes. The evolutionary advantage of maintaining copies of highly similar miRNAs is not well understood, nor is it clear what unique functions, if any, miRNA family members possess. Here, we study evolutionary...
Notch2 and Notch3 and elements of the Notch signaling network are dynamically expressed in developing follicles, where they are essential for normal granulosa cell proliferation and meiotic maturation. Notch receptors, ligands, and downstream effector genes are also expressed in testicular Leydig cells, predicting a potential role in regulating ste...
Background
Tissue-specific RNA plasticity broadly impacts the development, tissue identity and adaptability of all organisms, but changes in composition, expression levels and its impact on gene regulation in different somatic tissues are largely unknown. Here we developed a new method, polyA-tagging and sequencing (PAT-Seq) to isolate high-quality...
Lizards, which are amniote vertebrates like humans, are able to lose and regenerate a functional tail. Understanding the molecular basis of this process would advance regenerative approaches in amniotes, including humans. We have carried out the first transcriptomic analysis of tail regeneration in a lizard, the green anole Anolis carolinensis, whi...
Uniquely among amniote vertebrates, lizards can lose their tails and regrow a functional replacement. These regenerated tails, which have an organization distinct from the original tail, contain newly formed hyaline cartilage, muscle, vasculature, spinal cord, and skin. Using Illumina RNA‐Seq technology, we have identified over 300 differentially e...
Lizards can lose their tails and regrow a functional replacement, which is a unique feature among amniote vertebrates. These regenerated tails include newly formed hyaline cartilage, spinal cord, muscle, vasculature, and skin. Progress in studying the cellular and molecular mechanisms of lizard regeneration has been previously limited by lack of ge...
Background:
Dynamic alterations in cell shape, migration, and adhesion play a central role in tissue morphogenesis during embryonic development and congenital disease. The mesenchymal-to-epithelial transition that occurs during vertebrate somitogenesis is required for proper patterning of the axial musculoskeletal system. Somitic MET is initiated...
Significance
This study discloses a role for Numb in the activation and proliferation of adult muscle satellite cells and a unique function in the regulation of the muscle mass determinant Myostatin. Using two different genetic approaches to ablate Numb , one that ablated Numb in the myogenic lineage developmentally leading to reduced muscle mass....
Genomes of eusocial insects code for dramatic examples of phenotypic plasticity and social organization. We compared the genomes of seven ants, the honeybee, and various solitary insects to examine whether eusocial lineages share distinct features of genomic organization. Each ant lineage contains ~4,000 novel genes, but only 64 of these genes are...
This study investigates the gross anatomy of the original and the regenerated tail in the green anole (Anolis carolinensis). Dissections were conducted on 24 original and 13 regenerated tails. While the extrinsic muscles of the original tail in A. carolinensis are similar to those in other known Anolis lizard species, the extent of the origins of m...
This study provides a histological comparison of the mature regenerated and original tail of the lizard Anolis carolinensis. These data will provide a framework for future studies of this emerging model organism whose genome was recently published. This study demonstrated that the cartilage skeleton of the regenerated tail enclosed a spinal cord wi...
This study investigates the gross anatomy of the original and the regenerated tail in the green anole (Anolis carolinensis). Dissections were conducted on 24 original and 13 regenerated tails. While the extrinsic muscles of the original tail in A. carolinensis are similar to those in other known Anolis lizard species, the extent of the origins of m...
The homeobox transcription factor Mohawk (Mkx) is a potent transcriptional repressor expressed in the embryonic precursors of skeletal muscle, cartilage, and bone. MKX
has recently been shown to be a critical regulator of musculoskeletal tissue differentiation and gene expression; however,
the genetic pathways through which MKX functions and its DN...
The vertebral column derives from somites, which are transient paired segments of mesoderm that surround the neural tube in the early embryo. Somites are formed by a genetic mechanism that is regulated by cyclical expression of genes in the Notch, Wnt, and fibroblast growth factor (FGF) signaling pathways. These oscillators together with signaling...
Clinical studies have suggested that defects in the epaxial muscles, particularly multifidus, may contribute to the etiology of idiopathic scoliosis. While the epaxial muscles and the vertebrae derive from the same embryonic segmentation process, the mechanisms that pattern the multisegmental back muscles are still unclear. The process of segmentat...
Allurin, a 21 kDa protein isolated from egg jelly of the frog Xenopus laevis, has previously been demonstrated to attract frog sperm in two-chamber and microscopic assays. cDNA cloning and sequencing has shown that allurin is a truncated member of the Cysteine-Rich Secretory Protein (CRISP) family, whose members include mammalian sperm-binding prot...
The axial skeleton is a defining feature of vertebrates and is patterned during somitogenesis. Cyclically expressed members of the notch and other signaling pathways, described as the 'segmentation clock', regulate the formation of somite boundaries. Comparisons among vertebrate model systems have revealed fundamental shifts in the regulation of ex...
In the vertebrate embryo, skeletal muscle is derived from the myotome of the somites. Notch1-3 demonstrate overlapping and distinct expression patterns in mouse somites. Notch1 and Notch2 have been shown to be inhibitors of skeletal myogenesis. The current data demonstrate that Notch3 also is an effective inhibitor of MyoD induced myogenesis. Numb,...
A phylogenetic analysis of the basic helix-loop-helix (bHLH) gene superfamily was performed using seven different species (human, mouse, rat, worm, fly, yeast, and plant Arabidopsis) and involving over 600 bHLH genes (Stevens et al., 2008). All bHLH genes were identified in the genomes of the various species, including expressed sequence tags, and...
The vertebral column is composed of alternating vertebrae and intervertebral (IV) discs supported by robust spinal ligaments
and muscles. All of these elements, bony, cartilaginous, ligamentous, and muscular, are essential to the structural integrity
of the spine. The spine serves three vital functions: protecting the spinal cord and spinal nerves,...
Mutations in several regulatory genes along the Notch signaling pathway, including Lfng , are associated with vertebral defects and segmentation disorders. However, the role of these genes in regulating myogenic morphology is unknown. The objective of this study was to assess the role of Lfng in determining the morphology of paraspinal musculature....
Mohawk is an atypical homeobox gene expressed in embryonic progenitor cells of skeletal muscle, tendon, and cartilage. We demonstrate that Mohawk functions as a transcriptional repressor capable of blocking the myogenic conversion of 10T1/2 fibroblasts. The repressor activity is located in three small, evolutionarily conserved domains (MRD1-3) in t...
The cAMP response element binding protein/activating transcription factor (CREB/ATF) family of transcription factors is hormone responsive and critical for nearly all mammalian cell types. The basic helix-loop-helix (bHLH) family of transcription factors is important during the development and differentiation of a wide variety of cell types. Indepe...
Lunatic fringe belongs to a family of beta1-3 N-acetyltransferases that modulate the affinity of the Notch receptors for their ligands through the elongation of O-fucose moieties on their extracellular domain. A role for Notch signaling in vertebrate fertility has been predicted by the intricate expression of the Notch receptors and their ligands i...
Inborn Errors of Development is the definitive work on genetically caused abnormalities of human development. Despite the explosion in genetic advances, the causes of two-thirds of all birth defects remain unknown. However, we are on the brink of a revolution in this area, and this book is at the forefront. It is the first book to connect the disea...
Mesp2 and Paraxis are basic helix-loop-helix (bHLH) -type transcription factors coexpressed in the presomitic mesoderm (PSM) and are required for normal somite formation. Here, we show that Mesp2/Paraxis double-null mice exhibit a distinct phenotype unexpected from either Mesp2 or Paraxis single-null mice. In the posterior region of the body, most...
Homeodomain-containing proteins comprise a superfamily of transcription factors that participate in the regulation of almost all aspects of embryonic development. Here, we describe the mouse embryonic expression pattern of Mohawk, a new member of the TALE superclass of atypical homeobox genes that is most-closely related to the Iroquois class. Duri...
The alignment of the left-right (LR) body axis relative to the anteroposterior (AP) and dorsoventral (DV) axes is central to the organization of the vertebrate body plan and is controlled by the node/organizer. Somitogenesis plays a key role in embryo morphogenesis as a principal component of AP elongation. How morphogenesis is coupled to axis spec...
The regulation of cell adhesion in epithelia is a fundamental process governing morphogenesis in embryos and a key step in the progression of invasive cancers. Here, we have analysed the molecular pathways controlling the epithelial organisation of somites. Somites are mesodermal epithelial structures of vertebrate embryos that undergo several chan...
Recently, we cloned and sequenced the cDNA of allurin, a sperm chemoattractant isolated from the jelly of Xenopus laevis eggs [Proc. Natl. Acad. Sci. U.S.A. 78 (2001) 11205]. In this report, we demonstrate that allurin mRNA is expressed almost exclusively in the oviduct and that its expression is increased 2.5-fold by human chorionic gonadotropin o...
Members of the Twist subfamily of basic helix-loop-helix transcription factors are important for the specification of mesodermal derivatives during vertebrate embryogenesis. This subfamily includes both transcriptional activators such as scleraxis, Hand2, and Dermo-1 and repressors such as Twist and Hand1. Paraxis is a member of this subfamily, and...
Activating transcription factor 4 (ATF4/CREB2) is a member of the cyclic-AMP response element-binding (CREB) family. These proteins have been shown to regulate cell proliferation and differentiation in a broad number of tissues during embryo development. Here we report that male ATF4(-/-) mice are subfertile, despite the fact that they produce suff...
The anterior and posterior halves of individual somites adopt distinct fates during somitogenesis, which is crucial for establishing the metameric pattern of axial tissues such as the vertebral column and peripheral nerves. Genetic analyses have demonstrated that the specification of cells to an anterior or posterior fate is intimately related to t...
Folliculogenesis is the process of development of ovarian follicles that ultimately results in the release of fertilizable oocytes at ovulation. This is a complex program that involves the proliferation and differentiation of granulosa cells. Granulosa cells are necessary for follicle growth and support the oocyte during folliculogenesis. Genes tha...
Growth and differentiation of the mammalian oocyte is regulated with the coordinate development of the granulosa cells. The complex signaling pathways that regulate the growth and development of mammalian oocytes are beginning to be elucidated through the use of gene targeting. These technologies have provided new insight into the roles of specific...
Previously, we demonstrated that a protein from Xenopus egg jelly exhibits sperm chemoattractant activity when assayed by either video microscopy or by sperm passage across a porous filter. Here we describe the isolation and purification of allurin, the protein responsible for this activity. Freshly oviposited jellied eggs were soaked in buffer, an...
On Jan 10, 2011 this sequence version replaced gi:15987512.
Establishing the anterior/posterior (A/P) boundary of individual somites is important for setting up the segmental body plan of all vertebrates. Resegmentation of adjacent sclerotomes to form the vertebrae and selective migration of neural crest cells during the formation of the dorsal root ganglia and peripheral nerves occur in response to differe...
In vertebrates, skeletal muscle is derived from progenitor cell populations located in the epithelial dermomyotome compartment of the each somite. These cells become committed to the myogenic lineage upon delamination from the dorsomedial and dorsolateral lips of the dermomyotome and entry into the myotome or dispersal into the periphery. Paraxis i...
Segmentation of the paraxial mesoderm into somites requires a strategy distinct from the division of a preexisting field of cells, as seen in the segmentation of the vertebrate hindbrain into rhombomeres and the formation of the body plan of invertebrates. Each new somite forms from the anterior end of the segmental plate; therefore, the conditions...
The myogenic basic helix-loop-helix (bHLH) genes - MyoD, Myf5, myogenin and MRF4 - exhibit distinct, but overlapping expression patterns during development of the skeletal muscle lineage and loss-of-function mutations in these genes result in different effects on muscle development. MyoD and Myf5 have been shown to act early in the myogenic lineage...
A model to account for the role of Pax-3 in myogenesis is shown in Figure 2Figure 2. Not surprisingly, these new studies on the myogenic functions of Pax-3 raise as many questions as they answer. For example, how does Pax-3 activate MyoD expression? Is the MyoD gene a direct target for transcriptional activation by Pax-3 or are there intermediate s...
THE segmental organization of the vertebrate embryo is first apparent when somites form in a rostrocaudal progression from the paraxial mesoderm adjacent to the neural tube. Newly formed somites appear as paired epithelial spheres that become patterned to form vertebrae, ribs, skeletal muscle and dermis1–3. Paraxis is a basic helix–loop–helix trans...
The four myogenic basic helix-loop-helix proteins, MyoD, myogenin, Myf-5, and MRF4, can each activate skeletal muscle differentiation when introduced into nonmuscle cells. During embryogenesis, each of these genes is expressed in a unique but overlapping pattern in skeletal muscle precursors and their descendants. Gene knockout experiments have sho...
Terminal differentiation is coupled to withdrawal from the cell cycle. The cyclin-dependent kinase inhibitor (CKI) p21Cip1
is transcriptionally regulated by p53 and can induce growth arrest. CKIs are therefore potential mediators of developmental
control of cell proliferation. The expression pattern of mouse p21 correlated with terminal differentia...
We used an enzyme-linked immunosorbent assay to test sera from 186 cases of invasive cervical cancer and 172 age-matched controls for IgG and IgA antibodies to an human papillomavirus 16 E7 peptide and to peptide 245, representing an epitope in E2. Cases had significantly higher mean absorbance values than controls for both immunoglobulin isotypes...
The human papillomavirus type 16 E7 protein belongs to a family of nuclear oncoproteins that share amino acid sequences and functional homology. To localize biochemical activities associated with E7, we chemically synthesized the full-length 98-amino-acid polypeptide and several deletion mutant peptides. We show that the E7 polypeptide is biologica...
Early gene E5 of bovine papillomavirus type 1 encodes a 44-amino-acid protein whose expression can transform immortalized mouse cell lines. We have previously reported that a chemically synthesized E5 peptide functions to induce cellular DNA synthesis upon microinjection into growth-arrested mouse cells. We further defined the two E5 domains essent...
Thehumanpapillomavirus type16E7protein belongs toafamily ofnuclear oncoproteins thatshare amino acid sequencesandfunctional homology. Tolocalize biochemical activities associated withE7,we chemically synthesized thefull-length 98-amino-acid polypeptide andseveral deletion mutantpeptides. We showthat the E7polypeptide isbiologically active andposses...
The Notch signaling pathway has been demonstrated to be expressed in the mammalian testis during spermatogenesis. Sertoli cells have been demonstrated to express Jagged1 and Notch2. All four Notch receptors are expressed in developing spermatozoa (2,3) . We are interested in how the Notch signaling pathway impacts gametogenesis. The Lunatic fringe...
