1: Development. 2005 Jul;132(14):3243-53. 

Hedgehog signaling controls dorsoventral patterning, blastema cell proliferation
and cartilage induction during axolotl tail regeneration.

Schnapp E, Kragl M, Rubin L, Tanaka EM.

Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse
108, 01307 Dresden, Germany.

Tail regeneration in urodeles requires the coordinated growth and patterning of
the regenerating tissues types, including the spinal cord, cartilage and muscle.
The dorsoventral (DV) orientation of the spinal cord at the amputation plane
determines the DV patterning of the regenerating spinal cord as well as the
patterning of surrounding tissues such as cartilage. We investigated this
phenomenon on a molecular level. Both the mature and regenerating axolotl spinal
cord express molecular markers of DV progenitor cell domains found during
embryonic neural tube development, including Pax6, Pax7 and Msx1. Furthermore,
the expression of Sonic hedgehog (Shh) is localized to the ventral floor plate
domain in both mature and regenerating spinal cord. Patched1 receptor expression
indicated that hedgehog signaling occurs not only within the spinal cord but is
also transmitted to the surrounding blastema. Cyclopamine treatment revealed
that hedgehog signaling is not only required for DV patterning of the
regenerating spinal cord but also had profound effects on the regeneration of
surrounding, mesodermal tissues. Proliferation of tail blastema cells was
severely impaired, resulting in an overall cessation of tail regeneration, and
blastema cells no longer expressed the early cartilage marker Sox9. Spinal cord
removal experiments revealed that hedgehog signaling, while required for
blastema growth is not sufficient for tail regeneration in the absence of the
spinal cord. By contrast to the cyclopamine effect on tail regeneration,
cyclopamine-treated regenerating limbs achieve a normal length and contain
cartilage. This study represents the first molecular localization of DV
patterning information in mature tissue that controls regeneration.
Interestingly, although tail regeneration does not occur through the formation
of somites, the Shh-dependent pathways that control embryonic somite patterning
and proliferation may be utilized within the blastema, albeit with a different
topography to mediate growth and patterning of tail tissues during regeneration.

PMID: 15983402 [PubMed - indexed for MEDLINE]


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2: Dev Biol. 2004 Jul 15;271(2):439-66. 

Molecular anatomy of placode development in Xenopus laevis.

Schlosser G, Ahrens K.

Brain Research Institute, University of Bremen, 28334 Bremen, Germany.
gschloss@uni-bremen.de

We analyzed the spatiotemporal pattern of expression of 15 transcription factors
(Six1, Six4, Eya1, Sox3, Sox2, Pax6, Pax3, Pax2, Pax8, Dlx3, Msx1, FoxI1c, Tbx2,
Tbx3, Xiro1) during placode development in Xenopus laevis from neural plate to
late tail bud stages. Out of all genes investigated, only the expression of
Eya1, Six1, and Six4 is maintained in all types of placode (except the lens)
throughout embryonic development, suggesting that they may promote generic
placodal properties and that their crescent-shaped expression domain surrounding
the neural plate defines a panplacodal primordium from which all types of
placode originate. Double-labeling procedures were employed to reveal the
precise position of this panplacodal primordium relative to neural plate, neural
crest, and other placodal markers. Already at neural plate stages, the
panplacodal primordium is subdivided into several subregions defined by
particular combinations of transcription factors allowing us to identify the
approximate regions of origin of various types of placode. Whereas some types of
placode were already prefigured by molecularly distinct areas at neural plate
stages, the epibranchial, otic, and lateral line placodes arise from a common
posterior placodal area (characterized by Pax8 and Pax2 expression) and acquire
differential molecular signatures only after neural tube closure. Our findings
argue for a multistep mechanism of placode induction, support a combinatorial
model of placode specification, and suggest that different placodes evolved from
a common placodal primordium by successive recruitment of new inducers and
target genes.

PMID: 15223346 [PubMed - indexed for MEDLINE]


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3: Development. 2002 May;129(10):2459-72. 

BMP signaling patterns the dorsal and intermediate neural tube via regulation of
homeobox and helix-loop-helix transcription factors.

Timmer JR, Wang C, Niswander L.

Molecular Biology Program and Howard Hughes Medical Institute, Memorial
Sloan-Kettering Cancer Center, New York, NY 10021, USA.

In the spinal neural tube, populations of neuronal precursors that express a
unique combination of transcription factors give rise to specific classes of
neurons at precise locations along the dorsoventral axis. Understanding the
patterning mechanisms that generate restricted gene expression along the
dorsoventral axis is therefore crucial to understanding the creation of diverse
neural cell types. Bone morphogenetic proteins (BMPs) and other transforming
growth factor beta (TGFbeta) proteins are expressed by the dorsal-most cells of
the neural tube (the roofplate) and surrounding tissues, and evidence indicates
that they play a role in assigning cell identity. We have manipulated the level
of BMP signaling in the chicken neural tube to show that BMPs provide patterning
information to both dorsal and intermediate cells. BMP regulation of the
expression boundaries of the homeobox proteins Pax6, Dbx2 and Msx1 generates
precursor populations with distinct developmental potentials. Within the
resulting populations, thresholds of BMP act to set expression domain boundaries
of developmental regulators of the homeobox and basic helix-loop-helix (bHLH)
families, ultimately leading to the generation of a diversity of differentiated
neural cell types. This evidence strongly suggests that BMPs are the key
regulators of dorsal cell identity in the spinal neural tube.

PMID: 11973277 [PubMed - indexed for MEDLINE]


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4: Dev Biol. 2000 Nov 15;227(2):648-60. 

Dorsal and lateral fates in the mouse neural tube require the cell-autonomous
activity of the open brain gene.

Eggenschwiler JT, Anderson KV.

Molecular Biology Program, Sloan-Kettering Institute, 1275 York Avenue, New
York, New York 10021, USA.

The processes that specify early regional identity in dorsal and lateral regions
of the mammalian neural tube are not well understood. The mouse open brain (opb)
gene plays an essential role in dorsal neural patterning: in the caudal spinal
cord of opb mutants, dorsal cell types are absent and markers of ventral fates,
including Shh, expand into dorsal regions. Analysis of the opb mutant phenotype
and of opb/opb <--> wild-type chimeric embryos reveals that early in neural
development, the wild-type opb gene (opb(+)) is required cell autonomously for
the expression of Pax7 in dorsal cells and Pax6 in lateral cells. Thus the
opb(+) gene product acts intracellularly in the reception or interpretation of
signals that determine cell types in the dorsal 80% of the neural tube. At later
stages, the lack of opb(+) causes a non-cell-autonomous expansion of ventral
cell types into dorsal regions of the neural tube, revealing that opb(+)
controls the production of a diffusible molecule that defines the domain of Shh
expression. The data indicate that opb(+) could act as either a novel component
of a dorsalizing pathway or a novel intracellular negative regulator of the Shh
signal transduction pathway. Copyright 2000 Academic Press.

PMID: 11071781 [PubMed - indexed for MEDLINE]


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5: Trends Genet. 1999 Feb;15(2):59-65. 

Teeth. Where and how to make them.

Peters H, Balling R.

GSF-Research Center for Environment and Health, Institute for Mammalian
Genetics, Neuherberg, Germany. hpeters@rascal.med.harvard.edu

Organs have to develop at precisely determined sites to ensure functionality of
the whole organism. Organogenesis is typically regulated by a series of
interactions between morphologically distinct tissues. The developing tooth of
the mouse is an excellent model to study these processes and we are beginning to
understand the networks regulating reciprocal tissue interactions at the
molecular level. Synergistic and antagonistic effects of signaling molecules
including FGFs and BMPs are recursively used to induce localized responses in
the adjacent tissue layer (mesenchyme or epithelium). However, at different
phases of odontogenesis these secreted growth factors have distinct effects and
at the same time they are regulated by different upstream factors. The
mesenchymal transcription factors Msx1 and Pax9 are initially regulated by
epithelial FGFs and BMPs, but subsequently they function upstream of these
signaling molecules. This cascade provides a molecular model by which reciprocal
tissue interactions are controlled.

Publication Types:
    Review
    Review, Tutorial

PMID: 10098408 [PubMed - indexed for MEDLINE]


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6: Dev Genet. 1996;18(3):181-97. 

Genetic aspects of embryonic eye development in vertebrates.

Graw J.

Institut fur Saugetiergenetik, GSF-Forschungszentrum fur Umwelt und Gesundheit
Neuherberg, Oberschleissheim, Germany.

The vertebrate eye comprises tissues from different embryonic origins, e.g.,
iris and ciliary body are derived from the wall of the diencephalon via optic
vesicle and optic cup. Lens and cornea, on the other hand, come from the
overlying surface ectoderm. The timely action of transcription factors and
inductive signals ensure the correct development of the different eye
components. Establishing the genetic basis of eye defects has been an important
tool for the detailed analysis of this complex process. One of the main control
genes for eye development was discovered by the analysis of the allelic series
of the Small eye mouse mutants and characterized as Pax6. It is involved in the
interaction between the optic cup and the overlaying ectoderm. The central role
for Pax6 in eye development is conserved throughout the animal kingdom as the
murine Pax6 gene induces ectopic eyes in transgenic Drosophila despite the
obvious diverse organization of the eye in the fruit fly compared to
vertebrates. In human, mutations in the PAX6 gene are responsible for aniridia
and Peter's anomaly. In addition to Pax6, other mutations affecting the
interaction of the optic cup and the lens placode have been documented in the
mouse. For the differentiation of the retina from the optic cup several genes
are responsible: Mi leads to microphthalmia, if mutated, and encodes for a
transcription factor, which is expressed in the melanocytes of the pigmented
layer of the retina. In addition, further genes are implicated in the correct
development of the retina, e.g., Chx10, Dlx1, GH6, Msx1 and -2, Otx1 and -2, or
Wnt7b. Mutations within the retinoblastoma gene (RB1) are responsible for
retinal tumors. Knock-out mutants of RB1 exhibit a block of lens differentiation
prior to the retinal defect. Besides the influence of Rb1, the lens
differentiates under the influence of growth factors (e.g., FGF, IGF, PDGF,
TGF), and specific genes become activated encoding cytoskeletal proteins (e.g.,
filensin, phakinin, vimentin), structural proteins (e.g., crystallins) or
membrane proteins (e.g., Mip). The optic nerve originates from the neural
retina; ganglion cells grow to the optic stalk, forming the optic nerve. Its
retrograde walk to the brain through the rudiment of the optic stalk depends on
the correct Pax2 expression.

Publication Types:
    Review

PMID: 8631154 [PubMed - indexed for MEDLINE]


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