Publications by authors named "Peter Lonai"

11 Publications

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Fibroblast growth factor signaling and the function and assembly of basement membranes.

Authors:
Peter Lonai

Curr Top Dev Biol 2005 ;66:37-64

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel 76100.

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http://dx.doi.org/10.1016/S0070-2153(05)66002-4DOI Listing
September 2005

Laminin alpha1 globular domains 4-5 induce fetal development but are not vital for embryonic basement membrane assembly.

Proc Natl Acad Sci U S A 2005 Feb 24;102(5):1502-6. Epub 2005 Jan 24.

Department of Cell and Molecular Biology, Lund University, 22184 Lund, Sweden.

During early mouse embryogenesis, each laminin (Lm) chain of the first described Lm, a heterotrimer of alpha1, beta1, and gamma1 chains (Lm-1), is essential for basement membrane (BM) assembly, which is required for pregastrulation development. Individual domains may have other functions, not necessarily structural. The cell binding C terminus of Lm alpha1 chain contains five Lm globular (LG) domains. In vitro, alpha1LG1-3 domains bind integrins, and alpha1LG4 binds dystroglycan, heparin, and sulfatides. A prevailing hypothesis is that alpha1LG4 is crucial as a structural domain for BM assembly, whereas integrin-binding sites conduct signaling. The in vivo role of alpha1LG4-5 (also called E3) has not been studied. Mice lacking alpha1LG4-5 were therefore made. Null embryos implanted, but presumptive epiblast cells failed to polarize and did not survive past day 6.5. BM components including truncated Lm alpha1 were detected in Reichert's membrane. Surprisingly, embryonic BM assembly between visceral endoderm and stem cells was normal in null embryos and in embryoid bodies of alpha1LG4-5-null embryonic stem cells. Yet, stem cells could not develop into polarized epiblast cells. Thus, alpha1LG4-5 provides vital signals for the conversion of stem cells to polarized epithelium.
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http://dx.doi.org/10.1073/pnas.0405095102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC545491PMC
February 2005

Distinct GATA6- and laminin-dependent mechanisms regulate endodermal and ectodermal embryonic stem cell fates.

Development 2004 Nov 29;131(21):5277-86. Epub 2004 Sep 29.

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.

This study investigates the establishment of alternative cell fates during embryoid body differentiation when ES cells diverge into two epithelia simulating the pre-gastrulation endoderm and ectoderm. We report that endoderm differentiation and endoderm-specific gene expression, such as expression of laminin 1 subunits, is controlled by GATA6 induced by FGF. Subsequently, differentiation of the non-polar primitive ectoderm into columnar epithelium of the epiblast is induced by laminin 1. Using GATA6 transformed Lamc1-null endoderm-like cells, we demonstrate that laminin 1 exhibited by the basement membrane induces epiblast differentiation and cavitation by cell-to-matrix/matrix-to-cell interactions that are similar to the in vivo crosstalk in the early embryo. Pharmacological and dominant-negative inhibitors reveal that the cell shape change of epiblast differentiation requires ROCK, the Rho kinase. We also show that pluripotent ES cells display laminin receptors; hence, these stem cells may serve as target for columnar ectoderm differentiation. Laminin is not bound by endoderm derivatives; therefore, the sub-endodermal basement membrane is anchored selectively to the ectoderm, conveying polarity to its assembly and to the differentiation induced by it. Unique to these interactions is their flow through two cell layers connected by laminin 1 and their involvement in the differentiation of two epithelia from the same stem cell pool: one into endoderm controlled by FGF and GATA6; and the other into epiblast regulated by laminin 1 and Rho kinase.
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http://dx.doi.org/10.1242/dev.01415DOI Listing
November 2004

Regulation of external genitalia development by concerted actions of FGF ligands and FGF receptors.

Anat Embryol (Berl) 2004 Sep 31;208(6):479-86. Epub 2004 Aug 31.

Center for Animal Resources and Development, Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, 860-0811 Kumamoto, Japan.

Members of the fibroblast growth factor (FGF) family play diverse roles during the development and patterning of various organs. In human and mice, 22 FGFs and four receptors derived from several splice variants are present. Redundant expression and function of FGF genes in organogenesis have been reported, but their roles in embryonic external genitalia, genital tubercle (GT), development have not been studied in detail. To address the role of FGF during external genitalia development, we have analyzed the expression of FGF genes (Fgf8, 9, 10) and receptor genes (Fgfr1, r2IIIb, r2IIIc) in GT of mice. Furthermore, Fgf10 and Fgfr2IIIb mutant mice were analyzed to elucidate their roles in embryonic external genitalia development. Fgfr2IIIb was expressed in urethral plate epithelium during GT development. Fgfr2IIIb mutant mice display urethral dysmorphogenesis. Marker gene analysis for urethral plate and bilateral mesenchymal formation suggests the existence of epithelial-mesenchymal interaction during urethral morphogenesis. Therefore, FGF10/FGFR2IIIb signals seem to constitute a developmental cascade for such morphogenesis.
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http://dx.doi.org/10.1007/s00429-004-0419-9DOI Listing
September 2004

A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis.

Proc Natl Acad Sci U S A 2004 Aug 17;101(34):12555-60. Epub 2004 Aug 17.

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot 76100, Israel.

The b and c variants of fibroblast growth factor receptor 2 (FGFR2) differ in sequence, binding specificity, and localization. Fgfr2b, expressed in epithelia, is required for limb outgrowth and branching morphogenesis, whereas the mesenchymal Fgfr2c variant is required by the osteocyte lineage for normal skeletogenesis. Gain-of-function mutations in human FGFR2c are associated with craniosynostosis syndromes. To confirm and extend this evidence, we introduced a Cys342Tyr replacement into Fgfr2c to create a gain-of-function mutation equivalent to a mutation in human Crouzon and Pfeiffer syndromes. Fgfr2c(C342Y/)(+) heterozygote mice are viable and fertile with shortened face, protruding eyes, premature fusion of cranial sutures, and enhanced Spp1 expression in the calvaria. Homozygous mutants display multiple joint fusions, cleft palate, and trachea and lung defects, and die shortly after birth. They show enhanced Cbfa1/Runx2 expression without significant change in chondrocyte-specific Ihh, PTHrP, Sox9, Col2a, or Col10a gene expression. Histomorphometric analysis and bone marrow stromal cell culture showed a significant increase of osteoblast progenitors with no change in osteoclastogenic cells. Chondrocyte proliferation was decreased in the skull base at embryonic day 14.5 but not later. These results suggest that long-term aspects of the mutant phenotype, including craniosynostosis, are related to the Fgfr2c regulation of the osteoblast lineage. The effect on early chondrocyte proliferation but not gene expression suggests cooperation of Fgfr2c with Fgfr3 in the formation of the cartilage model for endochondral bone.
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http://dx.doi.org/10.1073/pnas.0405031101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC515096PMC
August 2004

Enhancement of oligodendrocyte differentiation from murine embryonic stem cells by an activator of gp130 signaling.

Stem Cells 2004 ;22(3):344-54

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

Embryonic stem (ES) cells derived from the inner cell mass of blastocyst-stage embryos are a potential large scale source of oligodendrocytes and of their progenitors for transplantation into the central nervous system for the repair of demyelinating lesions. We found previously that interleukin-6 (IL-6) fused to its soluble receptor (IL-6R), a potent activator of the gp130 receptor, induces myelin gene expression in Schwann cells of embryonic dorsal root ganglia. Like leukemia inhibitory factor, IL-6R/IL-6 inhibits the differentiation of murine ES cells into embryoid bodies. In the present study, we show that this recombinant cytokine may be efficiently used to stimulate the differentiation of oligodendrocytes if added to ES cell-derived neural precursors. IL-6R/IL-6 leads to an increase in early chondroitin sulfate proteoglycan positive and late O4 positive progenitors and to a stimulation of maturation into O1 and myelin basic protein expressing oligodendrocytes. Expression of the genes for transcription factor genes Olig-1 and Sox10, which appear early in the oligodendrocyte lineage, was stimulated by IL-6R/IL-6 addition. We conclude that this cytokine can significantly enhance the derivation of oligodendrocytes from ES cells.
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http://dx.doi.org/10.1634/stemcells.22-3-344DOI Listing
October 2005

Novel roles of Fgfr2 in AER differentiation and positioning of the dorsoventral limb interface.

Development 2003 Nov 24;130(22):5471-9. Epub 2003 Sep 24.

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.

The epithelial b variant of Fgfr2 is active in the entire surface ectoderm of the early embryo, and later in the limb ectoderm and AER, where it is required for limb outgrowth. As limb buds do not form in the absence of Fgfr2, we used chimera analysis to investigate the mechanism of action of this receptor in limb development. ES cells homozygous for a loss-of-function mutation of Fgfr2 that carry a beta-galactosidase reporter were aggregated with normal pre-implantation embryos. Chimeras with a high proportion of mutant cells did not form limbs, whereas those with a moderate proportion formed limb buds with a lobular structure and a discontinuous AER. Where present, the AER did not contain mutant cells, although mutant cells did localize to the adjacent surface ectoderm and limb mesenchyme. In the underlying mesenchyme of AER-free areas, cell proliferation was reduced, and transcription of Shh and Msx1 was diminished. En1 expression in the ventral ectoderm was discontinuous and exhibited ectopic dorsal localization, whereas Wnt7a expression was diminished in the dorsal ectoderm but remained confined to that site. En1 and Wnt7a were not expressed in non-chimeric Fgfr2-null mutant embryos, revealing that they are downstream of Fgfr2. In late gestation chimeras, defects presented in all three limb segments as bone duplications, bone loss or ectopic outgrowths. We suggest that Fgfr2 is required for AER differentiation, as well as for En1 and Wnt7a expression. This receptor also mediates signals from the limb mesenchyme to the limb ectoderm throughout limb development, affecting the position and morphogenesis of precursor cells in the dorsal and ventral limb ectoderm, and AER.
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http://dx.doi.org/10.1242/dev.00795DOI Listing
November 2003

Expression and biological role of laminin-1.

Matrix Biol 2003 Mar;22(1):35-47

Department of Cell and Molecular Biology, BMC B12, Lund University, Sweden.

Of the approximately 15 laminin trimers described in mammals, laminin-1 expression seems to be largely limited to epithelial basement membranes. It appears early during epithelial morphogenesis in most tissues of the embryo, and remains present as a major epithelial laminin in some adult tissues. Previous organ culture studies with embryonic tissues have suggested that laminin-1 is important for epithelial development. Recent data using genetically manipulated embryonic stem (ES) cells grown as embryoid bodies provide strong support for the view of a specific role of laminin-1 in epithelial morphogenesis. One common consequence of genetic ablation of FGF signaling, beta1-integrin or laminin gamma1 chain expression in ES cells is the absence of laminin-1, which correlates with failure of BM assembly and epiblast differentiation. Partial but distinct rescue of epiblast differentiation has been achieved in all three mutants by exogenously added laminin-1. Laminin-1 contains several biologically active modules, but several are found in beta1 or gamma1 chains shared by at least 11 laminins. However, the carboxytermini of the alpha chains contain five laminin globular (LG) modules, distinct for each alpha chain. There is increasing evidence for a particular role of alpha1LG4 binding to its receptors for epithelial tubulogenesis. The biological roles of this and other domains of laminin-1 are currently being explored by genetic means. The pathways controlling laminin-1 synthesis have remained largely unknown, but recent advances raise the possibility that laminin-1 and collagen IV synthesis can be regulated by pro-survival kinases of the protein kinase B/Akt family.
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http://dx.doi.org/10.1016/s0945-053x(03)00015-5DOI Listing
March 2003

Epithelial mesenchymal interactions, the ECM and limb development.

Authors:
Peter Lonai

J Anat 2003 Jan;202(1):43-50

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.

It has been long since recognized that cellular interactions are not always direct, i.e. they do not always take place between cells contacting each other, or between cells that emit soluble factors and other cells, which respond to it. In contrast, cross-talk between cells is frequently based on signals attached to the extracellular matrix (ECM). Thus besides proximate cell-to-cell contact, certain interactions are mediated by the ECM in a sequence: cell-to-matrix, matrix-to-cell. ECM-mediated interactions may take place within a group or sheet of cells or across adjacent cell sheets. A modified mat-like ECM, the basement membrane, separates adjacent cell sheets and mediates their interactions. Since cell sheets separated by basement membranes are an elementary feature of metazoan histology, interactions with the basement membrane have considerable importance. Recently accumulated evidence emphasizes the importance of ECM-mediated interactions. It is becoming increasingly evident that the ECM functions not only as an architectural component, but it is involved also in signal transduction. This evidence derives from four main sources: from the structure of receptor-ligand complexes, from Drosophila and C elegans genetics, from cell biological observations and from the analysis of mammalian development. In this review, I will touch upon recent evidence, illustrated by examples of FGF signalling in vertebrate limb development. Although the involvement of matrix components is not yet proven for all cases directly, the strength of multiple indications suggests that a better understanding of ECM-mediated interactions will shed new light on cell differentiation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1571048PMC
http://dx.doi.org/10.1046/j.1469-7580.2003.00143.xDOI Listing
January 2003

Generation and phenotypic analysis of CHIF knockout mice.

Am J Physiol Renal Physiol 2002 Sep;283(3):F569-77

Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.

Corticosteroid hormone-induced factor (CHIF) is a short epithelial-specific protein that is independently induced by aldosterone and a high-K(+) diet. It is a member of the FXYD family of single-span transmembrane proteins that include phospholemman, Mat-8, and the gamma-subunit of Na(+)-K(+)-ATPase. A number of studies have suggested that these proteins are involved in the regulation of ion transport and, in particular, functionally interact with the Na(+)-K(+)-ATPase. The present study describes the characterization, targeted disruption, and phenotypic analysis of the mouse CHIF gene. The CHIF knockout mice are viable and not distinguishable from wild-type littermates under normal conditions. Under K(+) loading, they have a twofold higher urine volume and an increased glomerular filtration rate. Similar but smaller effects are observed in mice fed a low-Na(+) diet. Treating K(+)-loaded mice for 10 days with furosemide resulted in lethality in the knockout mice (17 of 39) but not in the wild-type group (1 of 39). The data are consistent with an effect of CHIF on the Na(+)-K(+)-ATPase that is specific to the outer and inner medullary duct, its major expression site.
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http://dx.doi.org/10.1152/ajprenal.00376.2001DOI Listing
September 2002

The IIIc alternative of Fgfr2 is a positive regulator of bone formation.

Development 2002 Aug;129(16):3783-93

Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot Israel.

Fibroblast growth factor receptor type 2 (FGFR2) plays major roles in development. Like FGFR1 and FGFR3, it exists as two splice variants, IIIb and IIIc. We have investigated in the mouse the function of FGFR2IIIc, the mesenchymal splice variant of FGFR2. Fgfr2IIIc is expressed in early mesenchymal condensates and in the periosteal collar around the cartilage models; later it is expressed in sites of both endochondral and intramembranous ossification. A translational stop codon inserted into exon 9 disrupted the synthesis of Fgfr2IIIc without influencing the localized transcription of Fgfr2IIIb, the epithelial Fgfr2 variant. The recessive phenotype of Fgfr2IIIc(-/-) mice was characterized initially by delayed onset of ossification, with continuing deficiency of ossification in the sphenoid region of the skull base. During subsequent stages of skeletogenesis, the balance between proliferation and differentiation was shifted towards differentiation, leading to premature loss of growth, synostosis in certain sutures of the skull base and in the coronal suture of the skull vault, with dwarfism in the long bones and axial skeleton. The retarded ossification was correlated with decrease in the localized transcription of the osteoblast markers secreted phosphoprotein 1 (Spp1) and Runx2/Cbfa1. A decrease in the domain of transcription of the chondrocyte markers Ihh and PTHrP (Pthlh) corresponded with a decrease in their transcripts in the proliferative and hypertrophic chondrocyte zones. These results suggest that Fgfr2IIIc is a positive regulator of ossification affecting mainly the osteoblast, but also the chondrocyte, lineages. This role contrasts with the negative role of Fgfr3, although recent reports implicate FGF18, a ligand for FGFR3IIIc and FGFR2IIIc, as a co-ordinator of osteogenesis via these two receptors.
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August 2002
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