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ScienceWeek
DEVELOPMENTAL BIOLOGY: EMBRYOGENESIS AND CADHERIN PATHWAYS.
Cadherins are a family of cell adhesion receptors that are crucial for the mutual association of vertebrate cells. Through their homophilic binding interactions, cadherins play a role in cell-sorting mechanisms, conferring adhesion specificities on cells. The regulated expression of cadherins also controls cell polarity and tissue morphology. Cadherins are thus considered to be important regulators of morphogenesis. Moreover, pathology studies suggest that the down-regulation of cadherin expression is associated with the invasiveness of tumor cells.
The following points are made by W. James Nelson and Roel Nusse (Science 2004 303:1483):
1) During embryogenesis, cells often acquire new identities as they migrate to new locations (1). Many of these morphogenetic changes are induced by extracellular ligands and their receptors (1-4). An important problem is to identify the signaling pathways that coordinate changes in gene expression with dynamic changes in cell adhesion and migration. Deregulation of these pathways is likely to lead to alterations in cell fate, adhesion, and migration, hallmarks of diseases such as cancer.
2) Although several growth factors are known to affect both gene expression and cell migration (3), recent focus has been on the Wnt signaling pathway. Wnts are powerful regulators of cell proliferation and differentiation, and their signaling pathway involves proteins that directly participate in both gene transcription and cell adhesion. The central player is beta-catenin, which is a transcription cofactor with T cell factor/lymphoid enhancer factor TCF/LEF in the Wnt pathway (2) and a structural adaptor protein linking cadherins to the actin cytoskeleton in cell-cell adhesion (5).
3) Wnts are secreted lipid-modified signaling proteins that influence multiple processes in animal development. Nineteen Wnt genes exist in mammalian genomes, and the diversity of their functions is exemplified by mutations that lead to developmental abnormalities ranging from stem cell loss to kidney and reproductive tract defects (2). Signaling is initiated by Wnt ligand binding to two receptor molecules, Frizzled proteins and lipoprotein receptor-related proteins 5 and 6 (LRP-5/6).
4) Conventional Wnt signaling causes beta-catenin accumulation in a complex with the transcription factor TCF/LEF that regulates target gene expression. In the absence of Wnt signaling, the level of beta-catenin is kept low through degradation of (cytoplasmic) beta-catenin that is in excess of binding sites, such as cadherins at the plasma membrane. Beta-catenin is targeted for ubiquitination and degradation in the 26S proteosome by paired phosphorylation through the serine/threonine kinases casein kinase I (CKI) and glycogen synthase-3 (GSK-3-beta) bound to a scaffolding complex of axin and adenomatous polyposis coli (APC) protein (2). Activation of Wnt signaling leads to inhibition of GSK-3 activity, resulting in accumulation of cytoplasmic (signaling) beta-catenin, which becomes available to bind the TCF/LEF family of transcription factors and to induce target gene expression (2). Thus, the key factors in beta-catenin signaling are its stabilization and accumulation in the cytoplasm.
5) In summary: The specification and proper arrangements of new cell types during tissue differentiation require the coordinated regulation of gene expression and precise interactions between neighboring cells. Of the many growth factors involved in these events, Wnts are particularly interesting regulators, because a key component of their signaling pathway, beta-catenin, also functions as a component of the cadherin complex, which controls cell-cell adhesion and influences cell migration. The authors assemble evidence of possible interrelations between Wnt and other growth factor signaling, beta-catenin functions, and cadherin-mediated adhesion.
References (abridged):
1. M. Affolter et al., Dev. Cell 4, 11 (2003)
2. K. Cadigan, R. Nusse, Genes Dev. 11, 3286 (1997)
3. J. P. Thiery, Nature Rev. Cancer 2, 442 (2002)
4. J. Massague, S. W. Blain, R. S. Lo, Cell 103, 295 (2000)
5. C. Jamora, E. Fuchs, Nature Cell Biol. 4, E101 (2002)
Science http://www.sciencemag.org
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ON CADHERINS AND MOTOR NEURON DEVELOPMENT
The following points are made by Sarah Guthrie (Current Biology 2002 12:R488):
1) The central nervous system exhibits a precise regional organization. Neurons that are morphologically and functionally similar are grouped together in layers, or in nuclei -- clusters of cell bodies that come in a variety of shapes and sizes. A particular variation of nuclear architecture is seen among motor neurons of the spinal cord, which are segregated into motor "pools". The defining feature of such a pool is that all its neurons send axons to a single muscle, and all receive input from a group of sensory (proprioceptive) neurons which innervate the same muscle target, sensing changes in muscle contraction. The simple circuit thus formed is the basis of the spinal stretch reflex.
2) Spinal motor neurons migrate from a common origin in the ventricular zone of the developing spinal cord to settle in their characteristic pools. So how are they sorted out? Recent work by Stephen Price and colleagues [1] implicates the cadherin cell adhesion molecules in the segregation process. Hints that cadherins might have roles in compartmentalizing neuronal populations came from their expression patterns in a number of regions of the nervous system [2-4] , and the observation that misexpression of cadherins disrupts partitioning of the cortex and striatum [5] . Price et al [1] cloned 15 chick cadherin genes and surveyed their expression in motor pools innervating the limb muscles, which can be defined by their expression of particular transcription factors. For example, adductor motor neurons express the Er81 and Islet-1 genes, while those of the external femorotibialis pool express Er81 but not Islet-1, and hip retractor motor neurons express Islet-1 but not Er81 [1].
3) Some cadherins were found to be expressed in most or all limb muscle motor neurons at their time of birth, but were later switched off in all but a subset of pools, while the expression of other cadherins was initiated after motor neuron birth in a pool-specific pattern [1] . In either case, pool segregation is accompanied by restricted cadherin expression, and individual pools express unique combinations of cadherins. Thus, adductor motor neurons express cadherins cad-8, MN-cad, T-cad and cad-6b; external femorotibialis motor neurons express cad-8, T-cad and cad-6b; and hip retractor motor neurons express cad-8 and cad-12. Since external femorotibialis and adductor motor neurons differ in the expression of only one cadherin, MN-cad, could this be causally related to motor pool sorting?
4) In summary: In the developing spinal cord, motor neurons become segregated into important functional units termed motor pools. Now it has been discovered that repertoires of cadherin surface molecules play key roles in motor pool sorting.
References (abridged):
1. Price S.R., DeMarco Garcia N.V., Ranscht B. and Jessell T.M. (2002) Regulation of motor pool sorting by differential expression of type II cadherins. Cell, 109:205-216
2. Suzuki S.C., Inoue T., Kimura V., Tanaka T. and Takeichi M. (1997) Neuronal circuits are subdivided by differential expression of Type-II classic cadherins in postnatal mouse brains. Mol. Cell. Neurosci., 9:433-447
3. Arndt K., Nakagawa S., Takeichi M. and Redies C. (1998) Cadherins define segments and parasagittal cell ribbons in the developing chick cerebellum. Mol. Cell. Neurosci., 10:211-228
4. Yoon M.S., Puelles L. and Redies C. (2000) Formation of cadherin-expressing brain nuclei in diencephalic alar plate divisions. J. Comp. Neurol., 427:461-480
5. Inoue T., Tanaka T., Takeichi M., Chisaka O., Nakamura S. and Osumi N. (2001) Role of cadherins in maintaining the compartment boundary between the cortex and striatum during development. Development, 128:561-569
Current Biology http://www.current-biology.com
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NEURAL CADHERIN AND HIPPOCAMPAL AXONAL SPROUTS.
The following points are made by W. Shan et al (J Neurosci Res 2002 69:292):
1) Aberrant mossy fiber sprouting and synaptic reorganization are plastic responses in human temporal lobe epilepsy, and in pilocarpine-induced epilepsy in rodents. Although the morphological features of the hippocampal epileptic reaction have been well documented, the molecular mechanisms underlying these structural changes are not understood.
2) The classic cadherins, calcium-dependent cell adhesion molecules, are known to function in development in neurite outgrowth, synapse formation, and stabilization. In pilocarpine-induced status epilepticus, the expression of N-cadherin mRNA was sharply upregulated and reached a maximum level (1- to 2.5-fold) at 1-to 4 weeks postseizure in the granule cell layer and the pyramidal cell layer of CA3. N-cadherin protein was correspondingly increased and became concentrated in the inner molecular layer of the dentate gyrus, consistent with the position of mossy fiber axonal sprouts. Moreover, N-cadherin labeling was punctate; colocalized with definitive synaptic markers, and partially localized on polysialated forms of neural cell adhesion molecule (PSA-NCAM)-positive dendrites of granule cells in the inner molecular layer.
3) The authors suggest their findings show that N-cadherin is likely to be a key factor in responsive synaptogenesis following status epilepticus, where it functions as a mediator of de novo synapse formation.
J. Neuroscience Research http://www.wileyeurope.com
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