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Kenneth M. Yamada - One of the best experts on this subject based on the ideXlab platform.

  • Retraction: Btbd7 is essential for region-specific epithelial cell dynamics and Branching Morphogenesis in vivo.
    Development (Cambridge England), 2020
    Co-Authors: William P. Daley, Shaohe Wang, Kenn Holmbeck, Kazue Matsumoto, Andrew D Doyle, Brian J Duchez, Kenneth M. Yamada
    Abstract:

    Branching Morphogenesis of developing organs requires coordinated but poorly understood changes in epithelial cell-cell adhesion and cell motility. We report that Btbd7 is a crucial regulator of Branching Morphogenesis in vivo. Btbd7 levels are elevated in peripheral cells of Branching epithelial end buds, where it enhances cell motility and cell-cell adhesion dynamics. Genetic ablation of Btbd7 in mice disrupts Branching Morphogenesis of salivary gland, lung and kidney. Btbd7 knockout results in more tightly packed outer bud cells, which display stronger E-cadherin localization, reduced cell motility and decreased dynamics of transient cell separations associated with cleft formation; inner bud cells remain unaffected. Mechanistic analyses using in vitro MDCK cells to mimic outer bud cell behavior establish that Btbd7 promotes loss of E-cadherin from cell-cell adhesions with enhanced migration and transient cell separation. Btbd7 can enhance E-cadherin ubiquitination, internalization, and degradation in MDCK and peripheral bud cells for regulating cell dynamics. These studies show how a specific regulatory molecule, Btbd7, can function at a local region of developing organs to regulate dynamics of cell adhesion and motility during epithelial Branching Morphogenesis.

  • Cell and matrix dynamics in Branching Morphogenesis
    Principles of Tissue Engineering, 2020
    Co-Authors: Shaimar R. González Morales, Kenneth M. Yamada
    Abstract:

    Abstract Branching Morphogenesis establishes the tree-like architecture of multiple organs during embryonic development. It requires coordinated, dynamic remodeling and signaling between tissues and the extracellular matrix (ECM). We review similarities and differences in the principles and mechanisms of three major examples of Branching Morphogenesis: lung, kidney, and salivary gland. These developing organs utilize interactions between embryonic epithelium, mesenchyme, and ECM, along with growth factor signaling, to generate distinct morphological architectures. The specific signaling molecules required and extent of stereotypic patterning of branches differ between these organs. Epithelial interactions with the basement membranes and other matrix proteins are also generally important, for example, for local remodeling to permit tissue expansion. Live-organ imaging and computational modeling are providing novel insights into the mechanical and signaling basis of Branching Morphogenesis. Combining multiple approaches will be necessary for deeper understanding of Branching and to apply recent mechanistic insights to tissue engineering.

  • Btbd7 is essential for region-specific epithelial cell dynamics and Branching Morphogenesis in vivo.
    Development (Cambridge England), 2017
    Co-Authors: William P. Daley, Shaohe Wang, Kenn Holmbeck, Kazue Matsumoto, Andrew D Doyle, Brian J Duchez, Kenneth M. Yamada
    Abstract:

    Branching Morphogenesis of developing organs requires coordinated but poorly understood changes in epithelial cell-cell adhesion and cell motility. We report that Btbd7 is a crucial regulator of Branching Morphogenesis in vivo. Btbd7 levels are elevated in peripheral cells of Branching epithelial end buds, where it enhances cell motility and cell-cell adhesion dynamics. Genetic ablation of Btbd7 in mice disrupts Branching Morphogenesis of salivary gland, lung and kidney. Btbd7 knockout results in more tightly packed outer bud cells, which display stronger E-cadherin localization, reduced cell motility and decreased dynamics of transient cell separations associated with cleft formation; inner bud cells remain unaffected. Mechanistic analyses using in vitro MDCK cells to mimic outer bud cell behavior establish that Btbd7 promotes loss of E-cadherin from cell-cell adhesions with enhanced migration and transient cell separation. Btbd7 can enhance E-cadherin ubiquitination, internalization, and degradation in MDCK and peripheral bud cells for regulating cell dynamics. These studies show how a specific regulatory molecule, Btbd7, can function at a local region of developing organs to regulate dynamics of cell adhesion and motility during epithelial Branching Morphogenesis.

  • Patterned cell and matrix dynamics in Branching Morphogenesis.
    The Journal of cell biology, 2017
    Co-Authors: Shaohe Wang, Rei Sekiguchi, William P. Daley, Kenneth M. Yamada
    Abstract:

    Many embryonic organs undergo Branching Morphogenesis to maximize their functional epithelial surface area. Branching Morphogenesis requires the coordinated interplay of multiple types of cells with the extracellular matrix (ECM). During Branching Morphogenesis, new branches form by “budding” or “clefting.” Cell migration, proliferation, rearrangement, deformation, and ECM dynamics have varied roles in driving budding versus clefting in different organs. Elongation of the newly formed branch and final maturation of the tip involve cellular mechanisms that include cell elongation, intercalation, convergent extension, proliferation, and differentiation. New methodologies such as high-resolution live imaging, tension sensors, and force-mapping techniques are providing exciting new opportunities for future research into Branching Morphogenesis.

  • Cleft formation and Branching Morphogenesis of salivary gland: exploration of new functional genes
    Interface Oral Health Science 2009, 2010
    Co-Authors: Takayoshi Sakai, Tomohiro Onodera, Kenneth M. Yamada
    Abstract:

    Epithelial Branching Morphogenesis is important to form many organs. Embryonic salivary glands provide an excellent model for clarifying the mechanisms of this phenomenon. As clefts form, epithelial cell–cell adhesions are converted to cell–matrix adhesions. Nevertheless, the mechanism of cleft formation is not well understood. Here, we describe a set of approaches being used to identify and characterize molecules necessary for Branching Morphogenesis. A combination of laser microdissection with T7-SAGE has been established as a gene discovery method for identifying candidate molecules that may be essential for early organ Morphogenesis. Progress in understanding the mechanisms of salivary Branching Morphogenesis will provide novel approaches to future tissue engineering or regeneration of damaged salivary glands.

Sanjay K. Nigam - One of the best experts on this subject based on the ideXlab platform.

  • Branching Morphogenesis and kidney disease.
    Development (Cambridge England), 2004
    Co-Authors: Mita M. Shah, Kevin T. Bush, Hiroyuki Sakurai, Rosemary V. Sampogna, Sanjay K. Nigam
    Abstract:

    Branching Morphogenesis in the kidney is a tightly regulated, complex process and its disruption potentially can lead to a broad spectrum of diseases, ranging from rare hereditary syndromes to common conditions such as hypertension and chronic kidney failure. This review synthesizes data on Branching during kidney development derived from in vitro and in vivo rodent studies and to apply them to human diseases. It discusses how the broad organization of molecular interactions during kidney development might provide a mechanistic framework for understanding disorders related to aberrant Branching.

  • Identification of pleiotrophin as a mesenchymal factor involved in ureteric bud Branching Morphogenesis
    Development (Cambridge England), 2001
    Co-Authors: Hiroyuki Sakurai, Kevin T. Bush, Sanjay K. Nigam
    Abstract:

    Branching Morphogenesis is central to epithelial organogenesis. In the developing kidney, the epithelial ureteric bud invades the metanephric mesenchyme, which directs the ureteric bud to undergo repeated Branching. A soluble factor(s) in the conditioned medium of a metanephric mesenchyme cell line is essential for multiple Branching Morphogenesis of the isolated ureteric bud. The identity of this factor had proved elusive, but it appeared distinct from factors such as HGF and EGF receptor ligands that have been previously implicated in Branching Morphogenesis of mature epithelial cell lines. Using sequential column chromatography, we have now purified to apparent homogeneity an 18 kDa protein, pleiotrophin, from the conditioned medium of a metanephric mesenchyme cell line that induces isolated ureteric bud Branching Morphogenesis in the presence of glial cell-derived neurotrophic factor. Pleiotrophin alone was also found to induce the formation of Branching tubules in an immortalized ureteric bud cell line cultured three-dimensionally in an extracellular matrix gel. Consistent with an important role in ureteric bud Morphogenesis during kidney development, pleiotrophin was found to localize to the basement membrane of the developing ureteric bud in the embryonic kidney. We suggest that pleiotrophin could act as a key mesenchymally derived factor regulating Branching Morphogenesis of the ureteric bud and perhaps other embryonic epithelial structures.

  • Matrix metalloproteinases and their inhibitors regulate in vitro ureteric bud Branching Morphogenesis.
    American journal of physiology. Renal physiology, 2000
    Co-Authors: Martin Pohl, Hiroyuki Sakurai, Kevin T. Bush, Sanjay K. Nigam
    Abstract:

    Mammalian kidney development is initiated by the mutual interaction between embryonic metanephric mesenchyme (MM) and the ureteric bud (UB), leading to tightly controlled UB Branching Morphogenesis. In a three-dimensional cell culture model, which employs MM cell-derived conditioned medium (BSN-CM) to induce UB cell Branching Morphogenesis in extracellular matrix (ECM) gels (Sakurai H, Barros EJ, Tsukamoto T, Barasch J, and Nigam SK. Proc Natl Acad Sci USA 94: 6279-6284, 1997), Branching Morphogenesis was inhibited by both chemical agents (ilomastat and 1,10-orthophenanthroline) and a physiological protein factor [tissue inhibitor of metalloproteinases (TIMP)-2], known to act as matrix metalloproteinase (MMP) inhibitors. In addition, UB Branching was inhibited in isolated UB culture (Qiao J, Sakurai H, and Nigam SK. Proc Natl Acad Sci USA 96: 7330-7335, 1999) by TIMP-2 and ilomastat, suggesting a direct role for MMPs in UB Branching. Gelatin zymography and enzymatic measurement of MMP activity revealed that MMPs could originate from at least three different sources: the conditioned medium, the ECM, and the UB cells themselves. In the UB cells, transcription of several MMPs [gelatinase A (MMP2) and B (MMP9), stromelysin (MMP3), MT1-MMP] and TIMPs was altered by BSN-CM and changed as more complex Branching structures formed. The ECM appeared to serve as both a reservoir for MMPs and modulated their expression because different ECM compositions altered the total MMP activity as well as specific subsets of MMPs expressed by the UB cells (as determined by zymography and Northern analysis). In the context of UB Branching Morphogenesis during kidney development, our data suggest a complex model in which soluble factors produced by the MM, in the context of specific ECM components, modulate the expression of specific subsets of MMPs and TIMPs in the UB, which alter as structures develop and the matrix environment changes. This suggests distinct roles for different subsets of MMPs and their inhibitors during different phases of Branching Morphogenesis.

  • Branching Morphogenesis during kidney development.
    Annual review of physiology, 2000
    Co-Authors: Martin Pohl, Robert O. Stuart, H. Sakurai, Sanjay K. Nigam
    Abstract:

    Epithelial tissues such as kidney, lung, and breast arise through Branching Morphogenesis of a pre-existing epithelial structure. They share common morphological stages and a need for regulation of a similar set of developmental decisions--where to start; when, where, and in which direction to branch; and how many times to branch--decisions requiring regulation of cell proliferation, apoptosis, invasiveness, and cell motility. It is likely that similar molecular mechanisms exist for the epithelial Branching program. Here we focus on the development of the collecting system of the kidney, where, from recent data using embryonic organ culture, cell culture models of Branching Morphogenesis, and targeted gene deletion experiments, the outlines of a working model for Branching Morphogenesis begin to emerge. Key Branching morphogenetic molecules in this model include growth factors, transcription factors, distal effector molecules (such as extracellular matrix proteins, integrins, proteinases and their inhibitors), and genes regulating apoptosis and cell proliferation.

  • Branching Morphogenesis independent of mesenchymal-epithelial contact in the developing kidney.
    Proceedings of the National Academy of Sciences of the United States of America, 1999
    Co-Authors: Jizeng Qiao, Hiroyuki Sakurai, Sanjay K. Nigam
    Abstract:

    Whether mesenchymal–epithelial interactions leading to Branching Morphogenesis in developing epithelial tissues such as the kidney require direct cell–cell contact or are due to soluble mediators elaborated by the inducing tissue has been the subject of much debate. Here we demonstrate that ureteric bud (UB) epithelium, from which the kidney collecting system and upper urinary tract are derived, can undergo impressive three-dimensional Branching Morphogenesis when cultured in the appropriate extracellular matrix context in the absence of direct contact with mesenchymal tissue, indicating that the program for Branching Morphogenesis is inherent to the UB. Both a soluble factor in BSN cell-conditioned medium (BSN-CM) derived from an immortalized cell line thought to originate in the early metanephric mesenchyme and glial cell line-derived neurotrophic factor (GDNF) were required for early and later events in Branching Morphogenesis. In the absence of BSN-CM, the isolated UB did not survive; a similar result was obtained in the presence of neutralizing antibodies against glial cell line-derived neurotrophic factor. Preliminary analysis of key activity present in BSN-CM indicates that it is a heat-sensitive, heparin-binding factor with a probable molecular mass greater than 100 kDa. When the in vitro cultured UB was recombined with freshly isolated metanephric mesenchyme, nephric units were induced in the mesenchyme, and the UB branches underwent elongation. Our data suggest that, although UB Branching Morphogenesis per se does not require direct mesenchymal contact, such contact may play a key role in regulating branch elongation and establishing the pattern of Branching. The results also suggest an approach to in vitro engineering of nephron.

Norman D. Rosenblum - One of the best experts on this subject based on the ideXlab platform.

  • Renal Branching Morphogenesis
    Kidney Transplantation Bioengineering and Regeneration, 2017
    Co-Authors: Joshua Blake, Norman D. Rosenblum
    Abstract:

    The human kidney is composed of an arborized network of collecting ducts that converge at the urinary calyces and pelvis to facilitate urine excretion. The renal collecting system arises from the ureteric bud (UB), a derivative of the intermediate mesoderm–derived nephric duct that responds to inductive signals from adjacent tissues via a process termed ureteric induction. The UB subsequently undergoes a series of iterative Branching and remodeling events in a process termed renal Branching Morphogenesis. Formation of the renal collecting system is completed by the 34th week of gestation in humans. Perturbations in patterning of the nephric duct, ureteric induction, or renal Branching Morphogenesis leads to a spectrum of malformations collectively termed congenital anomalies of the kidney and urinary tract. In this chapter, we describe critical morphogenetic and cellular events that govern nephric duct specification, UB induction, renal Branching Morphogenesis, and cessation of renal Branching Morphogenesis.

  • Renal Branching Morphogenesis: Morphogenetic and signaling mechanisms
    Seminars in cell & developmental biology, 2014
    Co-Authors: Joshua Blake, Norman D. Rosenblum
    Abstract:

    The human kidney is composed of an arborized network of collecting ducts, calyces and urinary pelvis that facilitate urine excretion and regulate urine composition. The renal collecting system is formed in utero, completed by the 34th week of gestation in humans, and dictates final nephron complement. The renal collecting system arises from the ureteric bud, a derivative of the intermediate-mesoderm derived nephric duct that responds to inductive signals from adjacent tissues via a process termed ureteric induction. The ureteric bud subsequently undergoes a series of iterative Branching and remodeling events in a process called renal Branching Morphogenesis. Altered signaling that disrupts patterning of the nephric duct, ureteric induction, or renal Branching Morphogenesis leads to varied malformations of the renal collecting system collectively known as congenital anomalies of the kidney and urinary tract (CAKUT) and is the most frequently detected congenital renal aberration in infants. Here, we describe critical morphogenetic and cellular events that govern nephric duct specification, ureteric bud induction, renal Branching Morphogenesis, and cessation of renal Branching Morphogenesis. We also highlight salient molecular signaling pathways that govern these processes, and the investigative techniques used to interrogate them.

  • Stimulatory and inhibitory signaling molecules that regulate renal Branching Morphogenesis
    Pediatric Nephrology, 2009
    Co-Authors: Darren Bridgewater, Norman D. Rosenblum
    Abstract:

    Branching Morphogenesis, defined as the growth and Branching of epithelial tubules, is a fundamental developmental process involved in the formation of a variety of mammalian tissues, including the kidney. Defective renal Branching may result in a number of clinically relevant abnormalities, including renal agenesis, renal dysplasia, multiplex kidneys, and hypertension. In this review we describe the morphological events that generate the characteristic tree-like structure of the mammalian collecting system. We also highlight new knowledge related to both established and novel signaling systems that are important for stimulating and inhibiting Branching Morphogenesis.

  • Genetic Regulation of Branching Morphogenesis: Lessons Learned from Loss-of-Function Phenotypes
    Pediatric Research, 2003
    Co-Authors: Ming Chang Hu, Norman D. Rosenblum
    Abstract:

    Branching Morphogenesis, defined as growth and Branching of epithelial tubules during embryogenesis, is a fundamental feature of renal, lung, mammary gland, submandibular gland, and pancreatic Morphogenesis in mammals. Disruption of Branching Morphogenesis has been demonstrated to result in maldevelopment of some of these organs. Genetic studies performed in affected humans and mutant mice have implicated transcription factors, secreted growth factors, and cell surface signaling molecules as critical regulators of Branching Morphogenesis. These factors function within networks that appear to exert tight control over the number and location of branches. This review summarizes current knowledge regarding the molecular control of Branching Morphogenesis in vivo with particular emphasis on the genetic contribution to perturbed Branching Morphogenesis in mice and humans.

  • The molecular control of renal Branching Morphogenesis: current knowledge and emerging insights.
    Differentiation, 2002
    Co-Authors: Tino D. Piscione, Norman D. Rosenblum
    Abstract:

    Mammalian kidney development requires the formation of a patterned, branched network of collecting ducts, a process termed renal Branching Morphogenesis. Disruption of renal Branching Morphogenesis during human kidney development results in renal dysplasia, the major cause of renal failure in young children. Genetic evidence, combined with in vitro data, have implicated transcription factors, secreted growth factors, and cell surface signaling peptides as critical regulators of renal Branching Morphogenesis. This review discusses the current knowledge regarding the regulation of renal Branching Morphogenesis in vivo provided by the analysis of genetic mutations in mice and humans which disrupt collecting duct system development. In addition, in vivo and in vitro evidence regarding the functions of several other gene families are considered, rendering new insight into emerging regulatory roles for these molecules in renal Branching Morphogenesis.

Matthew P. Hoffman - One of the best experts on this subject based on the ideXlab platform.

  • The function of heparan sulfate during Branching Morphogenesis.
    Matrix biology : journal of the International Society for Matrix Biology, 2016
    Co-Authors: Vaishali N. Patel, Dallas L Pineda, Matthew P. Hoffman
    Abstract:

    Branching Morphogenesis is a fundamental process in the development of diverse epithelial organs such as the lung, kidney, liver, pancreas, prostate, salivary, lacrimal and mammary glands. A unifying theme during organogenesis is the importance of epithelial cell interactions with the extracellular matrix (ECM) and growth factors (GFs). The diverse developmental mechanisms giving rise to these epithelial organs involve many organ-specific GFs, but a unifying paradigm during organogenesis is the regulation of GF activity by heparan sulfates (HS) on the cell surface and in the ECM. This primarily involves the interactions of GFs with the sulfated side-chains of HS proteoglycans. HS is one of the most diverse biopolymers and modulates GF binding and signaling at the cell surface and in the ECM of all tissues. Here, we review what is known about how HS regulates Branching Morphogenesis of epithelial organs with emphasis on the developing salivary gland, which is a classic model to investigate epithelial-ECM interactions. We also address the structure, biosynthesis, turnover and function of HS during organogenesis. Understanding the regulatory mechanisms that control HS dynamics may aid in the development of therapeutic interventions for diseases and novel strategies for tissue engineering and regenerative medicine.

  • mt2 mmp dependent release of collagen iv nc1 domains regulates submandibular gland Branching Morphogenesis
    Developmental Cell, 2009
    Co-Authors: Ivan T. Rebustini, Christopher Myers, Keyonica S Lassiter, Andrew Surmak, Ludmila Szabova, Kenn Holmbeck, Vadim Pedchenko, Billy G Hudson, Matthew P. Hoffman
    Abstract:

    Summary Proteolysis is essential during Branching Morphogenesis, but the roles of MT-MMPs and their proteolytic products are not clearly understood. Here, we discover that decreasing MT-MMP activity during submandibular gland Branching Morphogenesis decreases proliferation and increases collagen IV and MT-MMP expression. Specifically, reducing epithelial MT2-MMP profoundly decreases proliferation and Morphogenesis, increases Col4a2 and intracellular accumulation of collagen IV, and decreases the proteolytic release of collagen IV NC1 domains. Importantly, we demonstrate the presence of collagen IV NC1 domains in developing tissue. Furthermore, recombinant collagen IV NC1 domains rescue Branching Morphogenesis after MT2-siRNA treatment, increasing MT-MMP and proproliferative gene expression via β1 integrin and PI3K-AKT signaling. Additionally, HBEGF also rescues MT2-siRNA treatment, increasing NC1 domain release, proliferation, and MT2-MMP and Hbegf expression. Our studies provide mechanistic insight into how MT2-MMP-dependent release of bioactive NC1 domains from collagen IV is critical for integrating collagen IV synthesis and proteolysis with epithelial proliferation during Branching Morphogenesis.

  • Salivary gland Branching Morphogenesis.
    Differentiation; research in biological diversity, 2006
    Co-Authors: Vaishali N. Patel, Ivan T. Rebustini, Matthew P. Hoffman
    Abstract:

    Salivary gland Branching Morphogenesis involves coordinated cell growth, proliferation, differentiation, migration, apoptosis, and interaction of epithelial, mesenchymal, endothelial, and neuronal cells. The ex vivo analysis of embryonic mouse submandibular glands, which branch so reproducibly and beautifully in culture, is a powerful tool to investigate the molecular mechanisms regulating epithelium-mesenchyme interactions during development. The more recent analysis of genetically modified mice provides insight into the genetic regulation of Branching Morphogenesis. The review begins, as did the field historically, focusing on the role of the extracellular matrix (ECM), and its components such as glycosaminoglycans, collagens, and laminins. Following sections describe the modification of the ECM by proteases and the role of cell-matrix and cell-cell receptors. The review then focuses on two major families of growth factors implicated in salivary gland development, the fibroblast growth factors (FGFs) and the epidermal growth factors (EGFs). The salivary gland phenotypes in mice with genetic modification of FGFs and their receptors highlight the central role of FGFs during salivary gland Branching Morphogenesis. A broader section mentions other molecules implicated from analysis of the phenotypes of genetically modified mice or organ culture experiments. The review concludes with speculation on some future areas of research.

  • Role of PI 3-kinase and PIP3 in submandibular gland Branching Morphogenesis
    Developmental biology, 2003
    Co-Authors: Melinda Larsen, Takayoshi Sakai, Matthew P. Hoffman, Justin C. Neibaur, Jonathan M. Mitchell, Kenneth M. Yamada
    Abstract:

    The mouse submandibular gland (SMG) epithelium undergoes extensive morphogenetic Branching during embryonic development as the first step in the establishment of its glandular structure. However, the specific signaling pathways required for SMG Branching Morphogenesis are not well understood. Using E13 mouse SMG organ cultures, we showed that inhibitors of phosphatidylinositol 3-kinase (PI 3-kinase), wortmannin and LY294002, substantially inhibited Branching Morphogenesis in SMG. Branching Morphogenesis of epithelial rudiments denuded of mesenchyme was inhibited similarly, indicating that PI 3-kinase inhibitors act directly on the epithelium. Immunostaining and Western analysis demonstrated that the p85 isoform of PI 3-kinase is expressed in epithelium at levels higher than in the mesenchyme. A target of PI 3-kinase, Akt/protein kinase B (PKB), showed decreased phosphorylation at Ser473 by Western analysis in the presence of PI 3-kinase inhibitors. The major lipid product of PI 3-kinase, phosphatidylinositol 3,4,5-trisphosphate (PIP3), was added exogenously to SMG via a membrane-transporting carrier in the presence of PI 3-kinase inhibitors and was found to stimulate cleft formation, the first step of Branching Morphogenesis. Together, these data indicate that PI 3-kinase plays a role in the regulation of epithelial Branching Morphogenesis in mouse SMG acting through a PIP3 pathway.

Melinda Larsen - One of the best experts on this subject based on the ideXlab platform.

  • The contribution of specific cell subpopulations to submandibular salivary gland Branching Morphogenesis
    Current Opinion in Genetics & Development, 2015
    Co-Authors: Hae Ryong Kwon, Melinda Larsen
    Abstract:

    Branching Morphogenesis is the developmental program responsible for generating a large surface to volume ratio in many secretory and absorptive organs. To accomplish Branching Morphogenesis, spatiotemporal regulation of specific cell subpopulations is required. Here, we review recent studies that define the contributions of distinct cell subpopulations to specific cellular processes during Branching Morphogenesis in the mammalian submandibular salivary gland, including the initiation of the gland, the coordination of cleft formation, and the contribution of stem/progenitor cells to Morphogenesis. In conclusion, we provide an overview of technological advances that have opened opportunities to further probe the contributions of specific cell subpopulations and to define the integration of events required for Branching Morphogenesis.

  • Heterotypic control of basement membrane dynamics during Branching Morphogenesis.
    Developmental biology, 2014
    Co-Authors: Deirdre A. Nelson, Melinda Larsen
    Abstract:

    Many mammalian organs undergo Branching Morphogenesis to create highly arborized structures with maximized surface area for specialized organ function. Cooperative cell–cell and cell–matrix adhesions that sculpt the emerging tissue architecture are guided by dynamic basement membranes. Properties of the basement membrane are reciprocally controlled by the interacting epithelial and mesenchymal cell populations. Here we discuss how basement membrane remodeling is required for Branching Morphogenesis to regulate cell–matrix and cell–cell adhesions that are required for cell patterning during Morphogenesis and how basement membrane impacts Morphogenesis by stimulation of cell patterning, force generation, and mechanotransduction. We suggest that in addition to creating mature epithelial architecture, remodeling of the epithelial basement membrane during Branching Morphogenesis is also essential to promote maturation of the stromal mesenchyme to create mature organ structure. Recapitulation of developmental cell–matrix and cell–cell interactions are of critical importance in tissue engineering and regeneration strategies that seek to restore organ function.

  • Cell and fibronectin dynamics during Branching Morphogenesis.
    Journal of Cell Science, 2006
    Co-Authors: Melinda Larsen, Cindy Wei, Kenneth M. Yamada
    Abstract:

    Branching Morphogenesis is a dynamic developmental process shared by many organs, but the mechanisms that reorganize cells during Branching Morphogenesis are not well understood. We hypothesized that extensive cell rearrangements are involved, and investigated cell migration using two-color confocal time-lapse microscopy to image cell and extracellular-matrix dynamics in developing salivary glands. We labeled submandibular salivary gland (SMG) epithelial cells with green fluorescent protein and matrix with fluorescent fibronectin. Surprisingly, we observed substantial, rapid and relatively random migration of individual epithelial cells during Branching Morphogenesis. We predicted that cell migration would decrease after formation of acini and, indeed, found that rapid cell movements do not occur in SMG from newborn mice. However, in embryonic SMG epithelial cells, we observed an absence of choreographed cell migration, indicating that patterned cell migration alone cannot explain the highly ordered process of Branching Morphogenesis. We therefore hypothesized a role for directional fibronection assembly in Branching. Washout and pulse-chase experiments revealed that older fibronectin accumulates at the base of the clefts and translocates inwards as a wedge, with newer fibronectin assembling behind it. These findings identify a new mechanism for Branching Morphogenesis involving directional fibronectin translocation superimposed on individual cell dynamics.

  • Salivary Gland Branching Morphogenesis : Exploration of Molecular Mechanisms Using Laser Microdissection and T7-SAGE
    Journal of Oral Biosciences, 2006
    Co-Authors: Takayoshi Sakai, Melinda Larsen, Mikihiko Kogo, Kenneth M. Yamada
    Abstract:

    Branching Morphogenesis is a key process utilized by many organs during embryonic development, but its mechanisms are not clearly understood. The developing submandibular salivary gland provides an excellent model system for clarifying the mechanisms comprising this phenomenon. Here we describe a recently developed set of approaches currently being used to identify and characterize molecules necessary for Branching Morphogenesis. The combination of laser microdissection with T7-SAGE is reviewed as a method for gene discovery of candidate molecules that may be essential for early organ Morphogenesis. We describe a current approach that promises to improve our understanding of the early morphological changes that occur during Branching Morphogenesis. This knowledge should facilitate development of future tissue engineering techniques and approaches to regenerating Branching organs.

  • fibronectin requirement in Branching Morphogenesis
    Nature, 2003
    Co-Authors: Takayoshi Sakai, Melinda Larsen, Kenneth M. Yamada
    Abstract:

    Many organs, including salivary glands, lung and kidney, are formed during embryonic development by epithelial Branching. In Branching Morphogenesis, repetitive epithelial cleft and bud formation create the complex three-dimensional Branching structures characteristic of many organs1,2,3. Although the mechanisms are poorly understood, one might involve the site-specific accumulation of some regulatory protein. Here we show that the extracellular matrix protein fibronectin4,5 is essential for cleft formation during the initiation of epithelial Branching. Fibronectin messenger RNA and fibrils appeared transiently and focally in forming cleft regions of submandibular salivary-gland epithelia, accompanied by an adjacent loss of cadherin localization. Decreasing the fibronectin concentration by using small interfering RNA and inhibition by anti-fibronectin or anti-integrin antibodies blocked cleft formation and Branching. Exogenous fibronectin accelerated cleft formation and Branching. Similar effects of fibronectin suppression and augmentation were observed in developing lung and kidney. Mechanistic studies revealed that fibrillar fibronectin can induce cell–matrix adhesions on cultured human salivary epithelial cells with a local loss of cadherins at cell–cell junctions. Thus, fibronectin expression is required for cleft formation in Branching Morphogenesis associated with the conversion of cell–cell adhesions to cell–matrix adhesions.