Scholars@Duke
John Archbold Klingensmith

John Archbold Klingensmith

Associate Professor of Cell Biology
Cell Biology
john.klingensmith@duke.edu
Box 90065, Durham, NC 27708
2127 Campus Drive, Duke University Graduate School, Durham, NC 27708

Selected Publications

Advance care planning with patients on hemodialysis: an implementation study.

Journal Article BMC Palliat Care · July 26, 2019 BACKGROUND: Patients with end-stage kidney disease (ESKD) on hemodialysis have limited life expectancy, yet their palliative care needs often go unmet. The aim of this study was to identify barriers and facilitators for implementation of "Shared Decision M ... Full text Link to item Cite

Shared decision-making in end-stage renal disease: a protocol for a multi-center study of a communication intervention to improve end-of-life care for dialysis patients.

Journal Article BMC Palliat Care · June 12, 2015 BACKGROUND: End-stage renal disease carries a prognosis similar to cancer yet only 20 % of end-stage renal disease patients are referred to hospice. Furthermore, conversations between dialysis team members and patients about end-of-life planning are uncomm ... Full text Link to item Cite

Sonic hedgehog from pharyngeal arch 1 epithelium is necessary for early mandibular arch cell survival and later cartilage condensation differentiation.

Journal Article Dev Dyn · April 2015 BACKGROUND: Morphogenesis of vertebrate craniofacial skeletal elements is dependent on a key cell population, the cranial neural crest cells (NCC). Cranial NCC are formed dorsally in the cranial neural tube and migrate ventrally to form craniofacial skelet ... Full text Link to item Cite

One shall become two: Separation of the esophagus and trachea from the common foregut tube.

Journal Article Dev Dyn · March 2015 The alimentary and respiratory organ systems arise from a common endodermal origin, the anterior foregut tube. Formation of the esophagus from the dorsal region and the trachea from the ventral region of the foregut primordium occurs by means of a poorly u ... Full text Link to item Cite

Multiple tissue-specific requirements for the BMP antagonist Noggin in development of the mammalian craniofacial skeleton.

Journal Article Dev Biol · August 15, 2014 Proper morphogenesis is essential for both form and function of the mammalian craniofacial skeleton, which consists of more than twenty small cartilages and bones. Skeletal elements that support the oral cavity are derived from cranial neural crest cells ( ... Full text Link to item Cite

BMP antagonism by Noggin is required in presumptive notochord cells for mammalian foregut morphogenesis.

Journal Article Dev Biol · July 1, 2014 Esophageal atresia with tracheoesophageal fistula (EA/TEF) is a serious human birth defect, in which the esophagus ends before reaching the stomach, and is aberrantly connected with the trachea. Several mouse models of EA/TEF have recently demonstrated tha ... Full text Link to item Cite

Development of the Craniofacial Skeleton

Chapter · July 19, 2013 This chapter summarizes current knowledge of normal craniofacial morphogenesis and the developmental basis of its major anomalies, focusing on craniofacial skeletal elements. Palatogenesis is a dynamic process, with each step crucial for proper development ... Full text Cite

Compartmentalization of the foregut tube: developmental origins of the trachea and esophagus.

Journal Article Wiley Interdiscip Rev Dev Biol · 2012 The mammalian trachea and esophagus share a common embryonic origin. They arise by compartmentalization of a single foregut tube, composed of foregut endoderm (FGE) and surrounding mesenchyme, around midgestation. Aberrant compartmentalization is thought t ... Full text Link to item Cite

RNA-binding protein FXR2 regulates adult hippocampal neurogenesis by reducing Noggin expression.

Journal Article Neuron · June 9, 2011 In adult mammalian brains, neurogenesis persists in the subventricular zone of the lateral ventricles (SVZ) and the dentate gyrus (DG) of the hippocampus. Although evidence suggest that adult neurogenesis in these two regions is subjected to differential r ... Full text Link to item Cite

Bone morphogenetic protein signaling is required in the dorsal neural folds before neurulation for the induction of spinal neural crest cells and dorsal neurons.

Journal Article Dev Dyn · April 2011 Bone Morphogenetic Protein (BMP) activity has been implicated as a key regulator of multiple aspects of dorsal neural tube development. BMP signaling in the dorsal-most neuroepithelial cells presumably plays a critical role. We use tissue-specific gene abl ... Full text Link to item Cite

The actin nucleator Cordon-bleu is required for development of motile cilia in zebrafish.

Journal Article Dev Biol · February 1, 2011 The cordon-bleu (Cobl) gene is widely conserved in vertebrates, with developmentally regulated axial and epithelial expression in mouse and chick embryos. In vitro, Cobl can bind monomeric actin and nucleate formation of unbranched actin filaments, while i ... Full text Link to item Cite

Modulation of BMP signaling by Noggin is required for the maintenance of palatal epithelial integrity during palatogenesis.

Journal Article Dev Biol · November 1, 2010 BMP signaling plays many important roles during organ development, including palatogenesis. Loss of BMP signaling leads to cleft palate formation. During development, BMP activities are finely tuned by a number of modulators at the extracellular and intrac ... Full text Link to item Cite

BMP antagonism protects Nodal signaling in the gastrula to promote the tissue interactions underlying mammalian forebrain and craniofacial patterning.

Journal Article Hum Mol Genet · August 1, 2010 Holoprosencephaly (HPE) is the most common forebrain and craniofacial malformation syndrome in humans. The genetics of HPE suggest that it often stems from a synergistic interaction of mutations in independent loci. In mice, several combinations of mutatio ... Full text Link to item Cite

Bone morphogenetic protein 4 mediates myocardial ischemic injury through JNK-dependent signaling pathway.

Journal Article J Mol Cell Cardiol · June 2010 Bone morphogenetic protein (BMP) signaling regulates embryonic development of many organ systems and defective BMP signaling has been implicated in adult disorders of many of these systems. However, its relevance in cardiac disease has not been reported. H ... Full text Link to item Cite

Roles of bone morphogenetic protein signaling and its antagonism in holoprosencephaly.

Journal Article Am J Med Genet C Semin Med Genet · February 15, 2010 Holoprosencephaly (HPE) is the most common malformation of the forebrain, resulting from a failure to completely septate the left and right hemispheres at the rostral end of the neural tube. Because of the tissue interactions that drive head development, t ... Full text Link to item Cite

Craniofacial Growth and Development

Journal Article · December 23, 2009 Full text Cite

Chordin is a modifier of tbx1 for the craniofacial malformations of 22q11 deletion syndrome phenotypes in mouse.

Journal Article PLoS Genet · February 2009 Point mutations in TBX1 can recapitulate many of the structural defects of 22q11 deletion syndromes (22q11DS), usually associated with a chromosomal deletion at 22q1.2. 22q11DS often includes specific cardiac and pharyngeal organ anomalies, but the presenc ... Full text Link to item Cite

An FGF autocrine loop initiated in second heart field mesoderm regulates morphogenesis at the arterial pole of the heart.

Journal Article Development · November 2008 In order to understand how secreted signals regulate complex morphogenetic events, it is crucial to identify their cellular targets. By conditional inactivation of Fgfr1 and Fgfr2 and overexpression of the FGF antagonist sprouty 2 in different cell types, ... Full text Link to item Cite

BMP antagonism is required in both the node and lateral plate mesoderm for mammalian left-right axis establishment.

Journal Article Development · August 2008 In mouse, left-right (L-R) patterning depends on asymmetric expression of Nodal around the node, leading to Nodal expression specifically in the left lateral plate mesoderm (LPM). Bone morphogenetic protein (BMP) signaling is also involved, but the mechani ... Full text Link to item Cite

Intracardiac septation requires hedgehog-dependent cellular contributions from outside the heart.

Journal Article Development · May 2008 Septation of the mammalian heart into four chambers requires the orchestration of multiple tissue progenitors. Abnormalities in this process can result in potentially fatal atrioventricular septation defects (AVSD). The contribution of extracardiac cells t ... Full text Link to item Cite

Cordon-bleu is an actin nucleation factor and controls neuronal morphology.

Journal Article Cell · October 19, 2007 Despite the wealth of different actin structures formed, only two actin nucleation factors are well established in vertebrates: the Arp2/3 complex and formins. Here, we describe a further nucleator, cordon-bleu (Cobl). Cobl is a brain-enriched protein usin ... Full text Link to item Cite

Neural plate morphogenesis during mouse neurulation is regulated by antagonism of Bmp signalling.

Journal Article Development · September 2007 Dorsolateral bending of the neural plate, an undifferentiated pseudostratified epithelium, is essential for neural tube closure in the mouse spinal region. If dorsolateral bending fails, spina bifida results. In the present study, we investigated the molec ... Full text Link to item Cite

Independent requirements for Hedgehog signaling by both the anterior heart field and neural crest cells for outflow tract development.

Journal Article Development · April 2007 Cardiac outflow tract (OFT) septation is crucial to the formation of the aortic and pulmonary arteries. Defects in the formation of the OFT can result in serious congenital heart defects. Two cell populations, the anterior heart field (AHF) and cardiac neu ... Full text Link to item Cite

The bone morphogenetic protein antagonist noggin regulates mammalian cardiac morphogenesis.

Journal Article Circ Res · February 2, 2007 Bone morphogenetic proteins (BMPs) play many roles in mammalian cardiac development. Here we address the functions of Noggin, a dedicated BMP antagonist, in the developing mouse heart. In early cardiac tissues, the Noggin gene is mainly expressed in the my ... Full text Link to item Cite

BMP signaling in the epiblast is required for proper recruitment of the prospective paraxial mesoderm and development of the somites.

Journal Article Development · October 2006 Bmpr1a encodes the BMP type IA receptor for bone morphogenetic proteins (BMPs), including 2 and 4. Here, we use mosaic inactivation of Bmpr1a in the epiblast of the mouse embryo (Bmpr-MORE embryos) to assess functions of this gene in mesoderm development. ... Full text Link to item Cite

Morphogenesis of the trachea and esophagus: current players and new roles for noggin and Bmps.

Journal Article Differentiation · September 2006 The development of the anterior foregut of the mammalian embryo involves changes in the behavior of both the epithelial endoderm and the adjacent mesoderm. Morphogenetic processes that occur include the extrusion of midline notochord cells from the epithel ... Full text Link to item Cite

Endogenous bone morphogenetic protein antagonists regulate mammalian neural crest generation and survival.

Journal Article Dev Dyn · September 2006 We demonstrate here that Chordin and Noggin function as bone morphogenetic protein (BMP) antagonists in vivo to promote mammalian neural crest development. Using Chrd and Nog single and compound mutants, we find that Noggin has a major role in promoting ne ... Full text Link to item Cite

Roles of organizer factors and BMP antagonism in mammalian forebrain establishment.

Journal Article Dev Biol · August 15, 2006 A critical question in mammalian development is how the forebrain is established. In amphibians, bone morphogenetic protein (BMP) antagonism emanating from the gastrula organizer is key. Roles of BMP antagonism and the organizer in mammals remain unclear. ... Full text Link to item Cite

The BMP antagonist Noggin promotes cranial and spinal neurulation by distinct mechanisms.

Journal Article Dev Biol · July 15, 2006 Here we characterize the consequences of elevated bone morphogenetic protein (BMP) signaling on neural tube morphogenesis by analyzing mice lacking the BMP antagonist, Noggin. Noggin is expressed dorsally in the closing neural folds and ventrally in the no ... Full text Link to item Cite

Fgf8 is required for anterior heart field development.

Journal Article Development · June 2006 In the mouse embryo, the splanchnic mesodermal cells of the anterior heart field (AHF) migrate from the pharynx to contribute to the early myocardium of the outflow tract (OT) and right ventricle (RV). Recent studies have attempted to distinguish the AHF f ... Full text Link to item Cite

Sonic hedgehog is required for cardiac outflow tract and neural crest cell development.

Journal Article Dev Biol · July 15, 2005 The Hedgehog signaling pathway is critical for a significant number of developmental patterning events. In this study, we focus on the defects in pharyngeal arch and cardiovascular patterning present in Sonic hedgehog (Shh) null mouse embryos. Our data ind ... Full text Link to item Cite

BMP receptor IA is required in the mammalian embryo for endodermal morphogenesis and ectodermal patterning.

Journal Article Dev Biol · June 1, 2004 BMPRIA is a receptor for bone morphogenetic proteins with high affinity for BMP2 and BMP4. Mouse embryos lacking Bmpr1a fail to gastrulate, complicating studies on the requirements for BMP signaling in germ layer development. Recent work shows that BMP4 pr ... Full text Link to item Cite

BMP receptor IA is required in mammalian neural crest cells for development of the cardiac outflow tract and ventricular myocardium.

Journal Article Development · May 2004 The neural crest is a multipotent, migratory cell population arising from the border of the neural and surface ectoderm. In mouse, the initial migratory neural crest cells occur at the five-somite stage. Bone morphogenetic proteins (BMPs), particularly BMP ... Full text Link to item Cite

The mammalian twisted gastrulation gene functions in foregut and craniofacial development.

Journal Article Dev Biol · March 15, 2004 Featured Publication Extracellular modulators of cell-cell signaling control numerous aspects of organismal development. The Twisted gastrulation (Twsg1) gene product is a small, secreted cysteine-rich protein that has the unusual property of being able to either enhance or in ... Full text Link to item Cite

Cordon-bleu is a conserved gene involved in neural tube formation.

Journal Article Dev Biol · October 1, 2003 Featured Publication The axial midline is an important source of patterning and morphogenesis cues in the vertebrate embryo. The midline derives from a small group of cells in the gastrulating embryo, known as "the organizer" in recognition of its ability to organize an entire ... Full text Link to item Cite

The role of chordin/Bmp signals in mammalian pharyngeal development and DiGeorge syndrome.

Journal Article Development · August 2003 Featured Publication The chordin/Bmp system provides one of the best examples of extracellular signaling regulation in animal development. We present the phenotype produced by the targeted inactivation of the chordin gene in mouse. Chordin homozygous mutant mice show, at low p ... Full text Link to item Cite

Chordin and noggin promote organizing centers of forebrain development in the mouse.

Journal Article Development · November 2002 Featured Publication In this study we investigate the roles of the organizer factors chordin and noggin, which are dedicated antagonists of the bone morphogenetic proteins (BMPs), in formation of the mammalian head. The mouse chordin and noggin genes (Chrd and Nog) are express ... Full text Link to item Cite

A novel mutation in the gene encoding noggin is not causative in human neural tube defects.

Journal Article J Neurogenet · 2002 Featured Publication Neural tube defects (NTD) are a common birth defect, with both genetic and environmental contributions to their etiology. In mouse, null mutations in Noggin result in fully-penetrant NTDs. We investigated Noggin for mutations that may predispose to human N ... Link to item Cite

The BMP antagonists Chordin and Noggin have essential but redundant roles in mouse mandibular outgrowth.

Journal Article Dev Biol · December 15, 2001 Featured Publication Here we investigate the roles of the Bone Morphogenetic Protein (BMP) antagonists Chordin and Noggin in development of the mandible, which is derived from the first branchial arch (BA1). Both genes are expressed in the pharynx during early mandibular outgr ... Full text Link to item Cite

The organizer factors Chordin and Noggin are required for mouse forebrain development.

Journal Article Nature · February 10, 2000 Featured Publication In mice, there is evidence suggesting that the development of head and trunk structures is organized by distinctly separated cell populations. The head organizer is located in the anterior visceral endoderm (AVE) and the trunk organizer in the node and ant ... Full text Link to item Cite

Neural induction and patterning in the mouse in the absence of the node and its derivatives.

Journal Article Dev Biol · December 15, 1999 Featured Publication The signals which induce vertebrate neural tissue and pattern it along the anterior-posterior (A-P) axis have been proposed to emanate from Spemann's organizer, which in mammals is a structure termed the node. However, mouse embryos mutant for HNF3 beta la ... Full text Link to item Cite

The segment polarity gene porcupine encodes a putative multitransmembrane protein involved in Wingless processing.

Journal Article Genes Dev · December 15, 1996 The Wnt protein Wingless (Wg) functions as a signal in patterning of both the Drosophila embryo and imaginal discs. Lack of porcupine (porc) activity is associated with mutant phenotypes similar to those of wg mutations. In porc mutant embryos, Wg protein ... Full text Link to item Cite

Regulation of flt-1 expression during mouse embryogenesis suggests a role in the establishment of vascular endothelium.

Journal Article Dev Dyn · September 1996 Flt-1 is a high affinity binding receptor for the vascular endothelial cell growth factor (VEGF) and is primarily expressed in endothelial cells. In this study we have investigated the temporal and spatial regulation of its expression by establishing mouse ... Full text Link to item Cite

Conservation of dishevelled structure and function between flies and mice: isolation and characterization of Dvl2.

Journal Article Mech Dev · August 1996 The segment polarity gene dishevelled (dsh) of Drosophila is required for pattern formation of the embryonic segments and the adult imaginal discs. dsh encodes the earliest-acting and most specific known component of the signal transduction pathway of Wing ... Full text Link to item Cite

A Drosophila CREB/CREM homolog encodes multiple isoforms, including a cyclic AMP-dependent protein kinase-responsive transcriptional activator and antagonist.

Journal Article Mol Cell Biol · September 1995 We have characterized a Drosophila gene that is a highly conserved homolog of the mammalian cyclic AMP (cAMP)-responsive transcription factors CREB and CREM. Uniquely among Drosophila genes characterized to date, it codes for a cAMP-responsive transcriptio ... Full text Link to item Cite

Dorsalizing and neuralizing properties of Xdsh, a maternally expressed Xenopus homolog of dishevelled.

Journal Article Development · June 1995 Signaling factors of the Wnt proto-oncogene family are implicated in dorsal axis formation during vertebrate development, but the molecular mechanism of this process is not known. Studies in Drosophila have indicated that the dishevelled gene product is re ... Full text Link to item Cite

Differential requirements for segment polarity genes in wingless signaling.

Journal Article Mech Dev · June 1995 The segment polarity genes wingless and engrailed are required throughout development of Drosophila. During early embryogenesis, these two genes are expressed in adjacent domains, in an inter-dependent way. Later, their expression is regulated by different ... Full text Link to item Cite

The dishevelled protein is modified by wingless signaling in Drosophila.

Journal Article Genes Dev · May 1, 1995 Wingless (Wg) is an important signaling molecule in the development of Drosophila, but little is known about its signal transduction pathway. Genetic evidence indicates that another segment polarity gene, dishevelled (dsh) is required for Wg signaling. We ... Full text Link to item Cite

Characterization of a gene trap insertion into a novel gene, cordon-bleu, expressed in axial structures of the gastrulating mouse embryo.

Journal Article Dev Genet · 1995 We have used a gene trap (GT) vector and embryonic stem (ES) cell chimeras to screen for insertions of the lacZ reporter gene into transcription units that are spatially and temporally regulated during early mouse embryogenesis. GT vectors which can act as ... Full text Link to item Cite

Signaling by wingless in Drosophila.

Journal Article Dev Biol · December 1994 Wingless, a member of the Wnt gene family, is an essential gene for segmentation in Drosophila, and is also involved in many other patterning events. The gene encodes a secreted protein that can regulate gene expression in adjacent cells. Recently, signifi ... Full text Link to item Cite

Isolation and characterization of a mouse homolog of the Drosophila segment polarity gene dishevelled.

Journal Article Dev Biol · November 1994 In the Drosophila embryo dishevelled (dsh) function is required by target cells in order to respond to wingless (wg, the homolog of Wnt-1), demonstrating a role for dsh in Wnt signal transduction. We have isolated a mouse homolog of the Drosophila dsh segm ... Full text Link to item Cite

dishevelled and armadillo act in the wingless signalling pathway in Drosophila.

Journal Article Nature · January 6, 1994 The Wnt genes encode conserved secreted proteins that play a role in normal development and tumorigenesis. Little is known about the signal transduction pathways of Wnt gene products. One of the best characterized Wnt family members is the Drosophila segme ... Full text Link to item Cite

The Drosophila segment polarity gene dishevelled encodes a novel protein required for response to the wingless signal.

Journal Article Genes Dev · January 1994 The Drosophila Wnt-1 homolog, wingless (wg), is involved in the signaling of patterning information in several contexts. In the embryonic epidermis, Wg protein is secreted and taken up by neighboring cells, in which it is required for maintenance of engrai ... Full text Link to item Cite

Mutations in the segment polarity genes wingless and porcupine impair secretion of the wingless protein.

Journal Article EMBO J · December 15, 1993 We have characterized the molecular nature of mutations in wingless (wg), a segment polarity gene acting during various stages of Drosophila development. Embryo-lethal alleles have undergone mutations in the protein-encoding domain of the gene, including d ... Full text Link to item Cite

Cell patterning in the Drosophila segment: engrailed and wingless antigen distributions in segment polarity mutant embryos.

Journal Article Development (Cambridge, England). Supplement · December 1, 1993 By a complex and little understood mechanism, segment polarity genes control patterning in each segment of the Drosophila embryo. During this process, cell to cell communication plays a pivotal role and is under direct control of the products of segment po ... Cite

Cell patterning in the Drosophila segment: engrailed and wingless antigen distributions in segment polarity mutant embryos.

Journal Article Dev Suppl · 1993 By a complex and little understood mechanism, segment polarity genes control patterning in each segment of the Drosophila embryo. During this process, cell to cell communication plays a pivotal role and is under direct control of the products of segment po ... Link to item Cite

The segment polarity phenotype of Drosophila involves differential tendencies toward transformation and cell death.

Journal Article Dev Biol · July 1989 The segment polarity genes of Drosophila are required for intrasegmental organization, as revealed by their abnormal cuticular morphology in mutant embryos. Lesions in most of these loci result in a similar cuticular phenotype, in which the normally naked, ... Full text Link to item Cite

Conservation of structure and location of Rhizobium meliloti and Klebsiella pneumoniae nifB genes.

Journal Article J Bacteriol · March 1987 Using transposon Tn5-mediated mutagenesis, an essential Rhizobium meliloti nitrogen fixation (nif) gene was identified and located directly downstream of the regulatory gene nifA. Maxicell and DNA sequence analysis demonstrated that the new gene is transcr ... Full text Link to item Cite