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Expression of Pax2 and patterning of the chick inner ear.

Early regionalized gene expression patterns within the otocyst appear to correlate with and contribute to development of mature otic structures. In the chick, the transcription factor Pax2 becomes restricted to the dorsal and entire medial side of the otocyst by stage 16/17. The dorsal region of the otocyst forms the endolymphatic duct and sac (ED/ES), and the cochlear duct is derived from the ventromedial region. In the mouse, however, Pax2 expression is reported only in the ventromedial and not the dorsal otocyst. In Pax2 null mice, the cochlea is missing or truncated, but vestibular structures differentiate normally. Here we demonstrate that in the chick, the emerging ED/ES express high levels of Pax2 even when the position of the emerging ED is altered with respect to its environment, either by 180 degrees otocyst rotations about the anterior/posterior axis or transplantation of the otocyst into the hindbrain cavity. However, the Pax2 expression pattern is plastic in the rest of the otic epithelium after 180 degrees rotation of the otocyst. Pax2 is upregulated on the medial side (formerly lateral), and downregulated on the lateral side (formerly medial and expressing Pax2) indicating that Pax2 expression is influenced by the environment. Although Pax2 is upregulated in the epithelium after 180 degrees rotations in the region that should form the cochlear duct, cochlear ducts are truncated or absent, and the ED/ES emerge in a new ventrolateral position. Ablation of the hindbrain at the placode or early otic pit stage alters the timing of regionalized Pax2 expression in the otocyst. The resulting otocysts and ears are generally smaller, vestibular structures are abnormal, ED/ES are missing but cochlear ducts are of normal length. The hindbrain and dorsal periotic mesenchyme provide unique trophic and patterning information to the dorsal otocyst. Our results demonstrate that the ED is the earliest structure patterned in the inner ear and that the hindbrain is important for its specification. We also show that, although normal Pax2 expression is required for cochlear duct development, it is downstream of ventral otocyst patterning events.

Animals↗
PubMed2006

Cell lineage transport: a mechanism for molecular gradient formation.

Gradient formation is a fundamental patterning mechanism during embryo development, commonly related to secreted proteins that move along an existing field of cells. Here, we mathematically address the feasibility of gradients of mRNAs and non-secreted proteins. We show that these gradients can arise in growing tissues whereby cells dilute and transport their molecular content as they divide and grow, a mechanism we termed 'cell lineage transport.' We provide an experimental test by unveiling a distal-to-proximal gradient of Hoxd13 in the vertebrate developing limb bud driven by cell lineage transport, corroborating our model. Our study indicates that gradients of non-secreted molecules exhibit a power-law profile and can arise for a wide range of biologically relevant parameter values. Dilution and nonlinear growth confer robustness to the spatial gradient under changes in the cell cycle period, but at the expense of sensitivity in the timing of gradient formation. We expect that gradient formation driven by cell lineage transport will provide future insights into understanding the coordination between growth and patterning during embryonic development.

Animals↗
PubMed2003

Deciphering skeletal patterning: clues from the limb.

Even young children can distinguish a Tyrannosaurus rex from a Brontosaurus by observing differences in bone size, shape, number and arrangement, that is, skeletal pattern. But despite our extensive knowledge about cartilage and bone formation per se, it is still largely a mystery how skeletal pattern is established. Much of what we do know has been learned from studying limb development in chicken and mouse embryos. Based on the data from such studies, models for how limb skeletal pattern is established have been proposed and continue to be hotly debated.

Animals↗
PubMed2003

A microRNA controlling left/right neuronal asymmetry in Caenorhabditis elegans.

How left/right functional asymmetry is layered on top of an anatomically symmetrical nervous system is poorly understood. In the nematode Caenorhabditis elegans, two morphologically bilateral taste receptor neurons, ASE left (ASEL) and ASE right (ASER), display a left/right asymmetrical expression pattern of putative chemoreceptor genes that correlates with a diversification of chemosensory specificities. Here we show that a previously undefined microRNA termed lsy-6 controls this neuronal left/right asymmetry of chemosensory receptor expression. lsy-6 mutants that we retrieved from a genetic screen for defects in neuronal left/right asymmetry display a loss of the ASEL-specific chemoreceptor expression profile with a concomitant gain of the ASER-specific profile. A lsy-6 reporter gene construct is expressed in less than ten neurons including ASEL, but not ASER. lsy-6 exerts its effects on ASEL through repression of cog-1, an Nkx-type homeobox gene, which contains a lsy-6 complementary site in its 3' untranslated region and that has been shown to control ASE-specific chemoreceptor expression profiles. lsy-6 is the first microRNA to our knowledge with a role in neuronal patterning, providing new insights into left/right axis formation.

3' Untranslated Regions↗
PubMed2006

CDMP1/GDF5 has specific processing requirements that restrict its action to joint surfaces.

CDMP1/GDF5 has not demonstrated biological activity in Xenopus embryos when overexpressed by mRNA injection. We provide biological and biochemical evidence that to become active, the protein requires cleavage by two distinct proteolytic enzymes. We demonstrate a specific overlap in the expression patterns of CDMP1/GDF5 with the proteases required to release the mature peptide at the location of the future articular surface but not in the future joint space. Taken together, these observations provide a plausible mechanism for local action of CDMP1/GDF5 consistent with requirements imposed by current models of pattern formation in the developing limb.

Amino Acid Sequence↗
PubMed1997

The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse.

Vertebrate animals exhibit segmented axial skeletons and lateral asymmetry of the visceral organs. The segment identity of individual vertebrae is believed to be determined by a combination of functionally active Hox genes that have defined expression boundaries along the anteroposterior axis (known as the axial Hox code). Disturbance of the Hox code by ectopic expression or mutation of Hox genes often leads to homeotic transformation of the vertebrae. Largely unknown, however, are the signaling molecules that provide the positional cues for the precise establishment and maintenance of the Hox code. In this study we show that disruption of the type IIB activin receptor (ActRIIB) by gene targeting results in altered expression of multiple Hox genes and abnormal patterning of the vertebrae, similar to but severer than retinoic acid (RA)-induced anterior transformation. We further show that RA and ActRIIB mutation have synergistic effects on vertebral patterning. Activin, Vg-1 and, type II activin receptors have been implicated in regulation of lateral asymmetry during chick and Xenopus development. We show here that the ActRIIB-/- mice die after birth with complicated cardiac defects including randomized heart position, malposition of the great arteries, and ventricular and atrial septal defects. In addition, the heart anomalies are associated with right pulmonary isomerism and splenic abnormalities, recapitulating the clinical symptoms of the human asplenia syndrome. These findings provide genetic evidence that the ActRIIB-mediated signaling pathway plays a critical role in patterning both anteroposterior and left-right axes in vertebrate animals.

Activin Receptors↗
PubMed2004

WNT signaling, in synergy with T/TBX6, controls Notch signaling by regulating Dll1 expression in the presomitic mesoderm of mouse embryos.

Notch signaling in the presomitic mesoderm (psm) is critical for somite formation and patterning. Here, we show that WNT signals regulate transcription of the Notch ligand Dll1 in the tailbud and psm. LEF/TCF factors cooperate with TBX6 to activate transcription from the Dll1 promoter in vitro. Mutating either T or LEF/TCF sites in the Dll1 promoter abolishes reporter gene expression in vitro as well as in the tail bud and psm of transgenic embryos. Our results indicate that WNT activity, in synergy with TBX6, regulates Dll1 transcription and thereby controls Notch activity, somite formation, and patterning.

Animals↗
PubMed2001

Notch inhibition of RAS signaling through MAP kinase phosphatase LIP-1 during C. elegans vulval development.

During Caenorhabditis elegans vulval development, a signal from the anchor cell stimulates the RTK/RAS/MAPK (receptor tyrosine kinase/RAS/mitogen-activated protein kinase) signaling pathway in the closest vulval precursor cell P6.p to induce the primary fate. A lateral signal from P6.p then activates the Notch signaling pathway in the neighboring cells P5.p and P7.p to prevent them from adopting the primary fate and to specify the secondary fate. The MAP kinase phosphatase LIP-1 mediates this lateral inhibition of the primary fate. LIN-12/NOTCH up-regulates lip-1 transcription in P5.p and P7.p where LIP-1 inactivates the MAP kinase to inhibit primary fate specification. LIP-1 thus links the two signaling pathways to generate a pattern.

Amino Acid Motifs↗
PubMed2005

Inactivation of the Sema5a gene results in embryonic lethality and defective remodeling of the cranial vascular system.

The semaphorins are a large family of proteins involved in the patterning of both the vascular and the nervous systems. In order to analyze the function of the membrane-bound semaphorin 5A (Sema5A), we generated mice homozygous for a null mutation in the Sema5a gene. Homozygous null mutants die between embryonic development days 11.5 (E11.5) and E12.5, indicating an essential role of Sema5A during embryonic development. Mutant embryos did not show any morphological defects that could account for the lethality of the mutation. A detailed analysis of the vascular system uncovered a role of Sema5A in the remodeling of the cranial blood vessels. In Sema5A null mutants, the complexity of the hierarchically organized branches of the cranial cardinal veins was decreased. Our results represent the first genetic analysis of the function of a class 5 semaphorin during embryonic development and identify a role of Sema5A in the regional patterning of the vasculature.

Animals↗
PubMed2003

Generating the cerebral cortical area map.

The view that the cortical primordium is initially patterned in similar ways to the rest of the embryo has been a conceptual breakthrough. We now have a new starting point for understanding how the cortical area map is established and how maps may change and evolve. Here we review findings that signaling molecules secreted from distinct cortical signaling centers establish positional information in the cortical primordium and regulate regional growth. In other embryonic systems, positional signals would regulate the patterned expression of transcription factors, leading, in a gene regulatory cascade, to the patterned differentiation of the tissue. We discuss candidate transcription factors with respect to such a model of cortical patterning. Finally, embryonic structures interact to pattern one another. We review data suggesting that the thalamus and cortex are patterned independently then interact to generate the final cortical area map.

Animals↗
PubMed2004

Odd-skipped related 2 (Osr2) encodes a key intrinsic regulator of secondary palate growth and morphogenesis.

Development of the mammalian secondary palate involves multiple steps of highly regulated morphogenetic processes that are frequently disturbed during human development, resulting in the common birth defect of cleft palate. Neither the molecular processes governing normal palatogenesis nor the causes of cleft palate is well understood. In an expression screen to identify new transcription factors regulating palate development, we previously isolated the odd-skipped related 2 (Osr2) gene, encoding a zinc-finger protein homologous to the Drosophila odd-skipped gene product, and showed that Osr2 mRNA expression is specifically activated in the nascent palatal mesenchyme at the onset of palatal outgrowth. We report that a targeted null mutation in Osr2 impairs palatal shelf growth and causes delay in palatal shelf elevation, resulting in cleft palate. Whereas palatal outgrowth initiates normally in the Osr2 mutant embryos, a significant reduction in palatal mesenchyme proliferation occurs specifically in the medial halves of the downward growing palatal shelves at E13.5, which results in retarded, mediolaterally symmetric palatal shelves before palatal shelf elevation. The developmental timing of palatal growth retardation correlates exactly with the spatiotemporal pattern of Osr1 gene expression during palate development. Furthermore, we show that the Osr2 mutants exhibit altered gene expression patterns, including those of Osr1, Pax9 and Tgfb3, during palate development. These data identify Osr2 as a key intrinsic regulator of palatal growth and patterning.

Animals↗
PubMed2004

Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung.

Cell fate and morphogenesis within the embryo is dependent upon secreted molecules that transduce signals between neighboring tissues. Reciprocal mesenchymal-epithelial interactions have proven essential during branching morphogenesis and cell differentiation within the lung; however, the interactions that result in lung specification from the foregut endoderm, prior to lung bud formation, are poorly understood. In this study, we investigate the tissue requirements and signals necessary for specification of a pulmonary cell fate using embryo tissue explants. We show that NKX2.1, an early transcription factor crucial for lung development, is expressed in the ventral foregut endoderm shortly after albumin and Pdx1, early markers of the liver and pancreas lineages, respectively. Similar to hepatic specification, direct contact of cardiac mesoderm with ventral endoderm is required to induce in vitro expression of NKX2.1 and downstream lung target genes including surfactant protein C and Clara cell secretory protein. In the absence of cardiac mesoderm, ventral foregut endoderm explants respond to exogenous fibroblast growth factor (FGF) 1 and FGF2 in a dose-dependent manner, with lower concentrations activating liver specific genes and higher concentrations activating lung specific genes. This signaling appears to be instructive, as the prospective dorsal midgut endoderm, which predominantly gives rise to the intestinal tract, is competent to respond to FGFs by inducing NKX2.1. Furthermore, the temporal expression and selective inhibition of FGF receptors 1 and 4 present within the endoderm implies that signaling through FGFR4 is involved in specifying lung versus liver. Together, the findings suggest that a concentration threshold of FGFs emanating from the cardiac mesoderm are involved in patterning the foregut endoderm.

Animals↗
PubMed1999

Frizzled and Dfrizzled-2 function as redundant receptors for Wingless during Drosophila embryonic development.

In cell culture assays, Frizzled and Dfrizzled2, two members of the Frizzled family of integral membrane proteins, are able to bind Wingless and transduce the Wingless signal. To address the role of these proteins in the intact organism and to explore the question of specificity of ligand-receptor interactions in vivo, we have conducted a genetic analysis of frizzled and Dfrizzled2 in the embryo. These experiments utilize a small gamma-ray-induced deficiency that uncovers Dfrizzled2. Mutants lacking maternal frizzled and zygotic frizzled and Dfrizzled2 exhibit defects in the embryonic epidermis, CNS, heart and midgut that are indistinguishable from those observed in wingless mutants. Epidermal patterning defects in the frizzled, Dfrizzled2 double-mutant embryos can be rescued by ectopic expression of either gene. In frizzled, Dfrizzled2 mutant embryos, ectopic production of Wingless does not detectably alter the epidermal patterning defect, but ectopic production of an activated form of Armadillo produces a naked cuticle phenotype indistinguishable from that produced by ectopic production of activated Armadillo in wild-type embryos. These experiments indicate that frizzled and Dfrizzled2 function downstream of wingless and upstream of armadillo, consistent with their proposed roles as Wingless receptors. The lack of an effect on epidermal patterning of ectopic Wingless in a frizzled, Dfrizzled2 double mutant argues against the existence of additional Wingless receptors in the embryo or a model in which Frizzled and Dfrizzled2 act simply to present the ligand to its bona fide receptor. These data lead to the conclusion that Frizzled and Dfrizzled2 function as redundant Wingless receptors in multiple embryonic tissues and that this role is accurately reflected in tissue culture experiments. The redundancy of Frizzled and Dfrizzled2 explains why Wingless receptors were not identified in earlier genetic screens for mutants defective in embryonic patterning.

Animals↗
PubMed2000

The role of the yolk syncytial layer in germ layer patterning in zebrafish.

Formation of the three germ layers requires a series of inductive events during early embryogenesis. Studies in zebrafish indicate that the source of these inductive signals may be the extra-embryonic yolk syncytial layer (YSL). The characterization of genes encoding the nodal-related factor, Squint, and homeodomain protein, Bozozok, both of which are expressed in the YSL, suggested that the YSL has a role in mesendoderm induction. However, these genes, and a second nodal-related factor, cyclops, are also expressed in the overlying marginal blastomeres, raising the possibility that the marginal blastomeres can induce mesendodermal genes independently of the YSL. We have developed a novel technique to study signaling from the YSL in which we specifically eliminate RNAs in the YSL, thus addressing the in vivo requirement of RNA-derived signals from this region in mesendoderm induction. We show that injection of RNase into the yolk cell after the 1K cell stage (3 hours) effectively eliminates YSL transcripts without affecting ubiquitously expressed genes in the blastoderm. We also present data that indicate the stability of existing proteins in the YSL is unaffected by RNase injection. Using this technique, we show that RNA in the YSL is required for the formation of ventrolateral mesendoderm and induction of the nodal-related genes in the ventrolateral marginal blastomeres, revealing the presence of an unidentified inducing signal released from the YSL. We also demonstrate that the dorsal mesoderm can be induced independently of signals from the YSL and present evidence that this is due to the stabilization of (&bgr;)-catenin in the dorsal marginal blastomeres. Our results demonstrate that germ layer formation and patterning in zebrafish uses a combination of YSL-dependent and -independent inductive events.

Animals↗
PubMed2005

Regulation of phyllotaxis.

Plant architecture is characterized by a high degree of regularity. Leaves, flowers and floral organs are arranged in regular patterns, a phenomenon referred to as phyllotaxis. Regular phyllotaxis is found in virtually all higher plants, from mosses, over ferns, to gymnosperms and angiosperms. Due to its remarkable precision, its beauty and its accessibility, phyllotaxis has for centuries been the object of admiration and scientific examination. There have been numerous hypotheses to explain the nature of the mechanistic principle behind phyllotaxis, however, not all of them have been amenable to experimental examination. This is due mainly to the delicacy and small size of the shoot apical meristem, where plant organs are formed and the phyllotactic patterns are laid down. Recently, the combination of genetics, molecular tools and micromanipulation has resulted in the identification of auxin as a central player in organ formation and positioning. This paper discusses some aspects of phyllotactic patterns found in nature and summarizes our current understanding of the regulatory mechanism behind phyllotaxis.

Biological Evolution↗
PubMed2005

Single-cell transcriptional profiles and spatial patterning of the mammalian olfactory epithelium.

In order to gain insights into the regulatory control of neuronal diversity in the mammalian olfactory system, we have identified the transcriptional profile of individual olfactory neurons. A single cell microarray strategy was performed to search for candidate genes involved in the molecular specification of dorso-ventral zones of olfactory receptor (OR) expression. Several transcripts were identified that display differential expression in distinct OR zones, including a novel family of genes, the Lozenge-like (Lzl) genes which share sequence consensus motifs with Lozenge, a transcription factor involved in the patterning of the Drosophila olfactory and visual systems.

Amino Acid Sequence↗
PubMed2000

Tumor patterning: analogies of neoplastic morphogenesis with embryogenesis.

Patterning or pattern formation is a spatial and temporal process, by which ordered arrangements of cells and tissue structure are attained. The term is mostly applied to the morphogenesis in developmental biology, but it can also be useful for the neomorphogenesis in tumor biology. Despite increasing data on the proliferation and differentiation of tumor cells, processes of tumor patterning are rarely studied and poorly understood. A fundamental embryonic process of patterning is the gastrulation and a basic example of neoplastic patterning is the colonic adenoma-carcinoma sequence. Both processes exhibit distinct nuclear translocations and expressions of beta-catenin, which is considered to be a decisive transcriptional regulator. Our recent studies demonstrate striking analogies of patterning and nuclear beta-catenin expressions between the colonic adenoma-carcinoma sequence and the gastrulation steps. The shared patterns are dissociation, reassembly, tubular reconstruction and branching of neoplastic cells in association with nuclear beta-catenin expressions. These new findings establish patterning as a relevant concept for tumor biology and link the neoplastic morphogenesis with embryogenesis.

Body Patterning↗
PubMed2004

Evo-devo aspects of classical and molecular data in a historical perspective.

We discuss the interplay between evolution and development as reflected in data and concepts since about 1800. Darwin and his "continental apostle" Haeckel put the striking similarity between early vertebrate embryos in an evolutionary context. Haeckel's partly illicit generalizations discredited evolutionary thinking among early experimental embryologists who moreover noted riddles incompatible with contemporary concepts of homology and evolution. Relevant solutions were suggested by the more recent concept of ontogenetic networks that embody complex regulatory properties and genes with partly overlapping functions. Molecular data on development increasingly reveal evolutionary opportunism, for instance when a widespread signaling chain involved in primitive immune defense was apparently recruited later on for dorso-ventral axis determination in some evolutionarily advanced insect groups. Recently, Rickettsia-related bacteria colonizing many arthropod species were found to "manipulate" the first steps of host development to the advantage of their own propagation, but by ways that could also promote host speciation. Molecular genetics can now document evolutionary steps in ontogenetic networks. In the fruit fly for instance, the novel bicoid gene has superseded a crucial patterning function within a pre-existing network--a case of "molecular caenogenesis." The expression patterns of conserved genes that antagonistically determine dorso-ventral polarity support a literal revolution envisioned almost 200 years ago. This is the dorso-ventral inversion of the body plan in some metazoans--ascribed then to the Articulata, now to the Chordata. The final section posits that the opportunistic character of evolutionary innovations is detrimental to parsimony in development.

Animals↗