1/f(p) Characteristics of the Fourier power spectrum affects ERP correlates of face learning and recognition.

We investigated the influence of Fourier power spectrum (1/f(p)) characteristics on face learning while recording ERPs that are associated with the representation of faces. Two image sets with an altered 1/f(p) characteristics were created. The first set consisted of stimuli with a STEEP SLOPE (1/f(3.5)) and therefore enhanced low spatial frequencies (LSF) and attenuated high spatial frequencies (HSF). The second set consisted of stimuli with a SHALLOW SLOPE (1/f(2)), similar to complex natural scenes and artwork, resulting in enhanced HSF and attenuated LSF. Faces with a SHALLOW SLOPE elicited larger N170 and N250 amplitudes and larger old/new effects for central positivity in comparison to unmodified faces. The opposite effect was observed for faces with a STEEP SLOPE that led to slower reaction times. This result suggests that diminishing the ratio of fine detail (HSF) to coarse structures (LSF) impairs face learning, whereas increasing it facilitates neurocognitive correlates of face learning.

Cadherin expression in the somatosensory cortex: evidence for a combinatorial molecular code at the single-cell level.

Cadherin superfamily genes play a role in a wide variety of developmental processes and mature functions of the vertebrate brain. In the present study, we mapped in situ the expression pattern of five classic cadherins (Cdh4, Cdh6, Cdh7, Cdh8, Cdh11) and eight δ-protocadherins (Pcdh1, Pcdh7, Pcdh8, Pcdh9, Pcdh10, Pcdh11, Pcdh17 and Pcdh19) in the primary somatosensory cortex of the adult mouse. All of these cadherins show layer-specific expression profiles in primary somatosensory cortex. Some cadherins (for example, Cdh4, Cdh7, Pcdh8) mark subsets of cells within a given lamina, while other cadherins (Cdh11 and Pcdh10) are expressed more widely in multiple layers. Results from tyramide-based double-fluorescence in situ hybridization (FISH) provide evidence that most single neurons express more than one cadherin in a combinatorial fashion in all layers of cerebral cortex. This combinatorial code is rather comprehensive because pairwise expression of cadherins can assume any type of combination (complementarity, partial or complete overlap, subset-specific expression, cell-size specific expression, etc.). We propose that the combinatorial expression of multiple cadherin genes contributes to the molecular specification of the vast complexity of neurons in cerebral cortex.

Cadherin-19 expression is restricted to myelin-forming cells in the chicken embryo.

We cloned chicken cadherin-19 that demonstrates high similarity to human and rat cadherin-19. Chicken cadherin-19 is a type II classic cadherin that is located on the long arm of chicken chromosome 2 and is composed of 13 exons and 12 introns. The expression profile of cadherin-19 was analyzed by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization during chicken embryonic development. Its expression starts at E2.5, then gradually increases to reach a peak at E20. In contrast to previous results obtained in rat, chicken cadherin-19 is expressed both in Schwann cells and oligodendrocytes, also at late stages of development. We found no other cell type positive for cadherin-19 in the chicken embryo throughout development, suggesting that cadherin-19 is selectively expressed by myelin-forming cells and might play a role in myelin formation. The sequence of cadherin-19 shares high similarity with that of cadherin-7 and cadherin-20, and the three genes form a cluster on chromosome 2. Their expression patterns, however, are rather distinct although partial overlap is observed. For example, cadherin-19 and cadherin-7 are co-expressed by Schwann cells but not by oligodendrocytes. Moreover, a subset of interneurons express cadherin-7 but not cadherin-19 or cadherin-20. Despite their close genetic relation, the three cadherins have acquired functions in rather different cell types during nervous system development.

Differential expression of five members of the ADAM family in the developing chicken brain.

ADAMs (a disintegrin and metalloprotease) are a family of trans-membrane multi-domain metalloproteases with multiple functions. So far, more than 35 ADAM family members have been identified from mammalian and nonmammalian sources. Although some functions of ADAMs have been elucidated, their expression patterns remain poorly investigated, especially during CNS development. Here, we cloned the open reading frames or full-length cDNAs of ADAM9, ADAM10, ADAM12, ADAM22 and ADAM23 from chicken embryonic brain, analyzed their evolutionary relationship, and mapped their expression in the embryonic chicken brain by in situ hybridization for the first time. In general, each of the five ADAMs shows a spatially restricted and temporally regulated expression profile. However, the types of tissues and cells, which express each of the five ADAMs, differ from each other. ADAM9 is predominantly expressed in the choroid plexus and in the ventricular layer. ADAM10 is expressed by developing blood vessels, oligodendrocytes, and subsets of neurons and brain nuclei. ADAM12 is expressed by very few brain nuclei, cerebellar Purkinje cells, restricted regions of the neuroepithelium, and some neurons in the deep tectal layers. ADAM22 expression is strong in some brain nuclei and in the pineal gland. ADAM23 is expressed by most gray matter regions and the choroid plexus. The differential expression patterns suggest that the five ADAMs play multiple and versatile roles during brain development.

Regionalized cadherin-7 expression by radial glia is regulated by Shh and Pax7 during chicken spinal cord development.

During development, several genes that specify neuronal subtype identity are expressed in distinct dorsoventral domains of the spinal cord and hindbrain. Cadherin-7 (Cad7), a member of the cadherin family of adhesion molecules, is expressed by radial glia in a dorsal domain of the spinal cord basal plate in chicken. To study the regulation of the Cad7 gene, we ectopically expressed two known dorsoventral patterning genes, Shh and Pax7, in the caudal neural tube and in two brain regions at different stages of development by in vivo electroporation. Results showed that Shh regulated the expression of Cad7 by radial glia in a concentration-dependent manner. Shh induced or repressed the expression of Cad7, at low and high concentrations, respectively. Furthermore, Pax7 inhibited the expression of Cad7. These results are compatible with a role of Shh and Pax7 in regulating endogenous Cad7 expression during spinal cord and hindbrain development. Our data show, for the first time, that Shh can regulate the expression not only of other gene regulatory factors, but also of Cad7, a morphoregulatory molecule that plays a role in axon elongation and neural circuit formation.

delta-Protocadherins: unique structures and functions.

delta-Protocadherins constitute a group of cadherins characterized by several conserved motifs in their cytoplasmic domains. We present a phylogenetic analysis that further divides this group into delta1-protocadherins (comprising protocadherin-1, -7, -9 and -11 or -X/Y) and delta2-protocadherins (comprising protocadherin-8, -10, -17, -18 and -19). The delta-protocadherin genes, which are located on different chromosomes in man and mouse, have a similar gene structure. They are expressed as multiple splice forms, differing mostly in their cytoplasmic domains. Some delta-protocadherins were reported to mediate weak cell-cell adhesion in vitro and cell sorting in vivo. In addition, individual delta-protocadherins might play important roles in signaling pathways, as they bind to proteins such as TAF1/Set, protein phosphatase-1alpha and the Frizzled 7 receptor. The spatiotemporally restricted expression of delta-protocadherins in different tissues and species and the results of their functional analysis, mainly in Xenopus, suggest that they play multiple, tightly regulated roles in vertebrate development.

delta-Protocadherins: a gene family expressed differentially in the mouse brain.

Phylogenetic analysis of protocadherin genes identified a new gene subfamily, the delta-protocadherins, containing several conserved motifs in their cytoplasmic domains. This subfamily can be further subdivided into two subgroups, named delta1-protocadherins (comprising protocadherin-1, -7, -9, and -11 or X/Y) and delta2-protocadherins (comprising protocadherin-8, -10, -17, -18, and -19). The members of the delta1-protocadherin subgroup were analyzed in greater detail here. They share a similar gene structure that results in the expression of multiple alternative transcripts. All members of this subgroup have at least one transcript that contains a binding site for protein phosphatase-1alpha. Like most classic cadherins, each of three delta1-protocadherins analyzed in this study by in situ hybridization showed a unique expression pattern that differed from the patterns of the other delta1-protocadherins. Together, these results suggest that the members of the delta1-protocadherin subgroup exercise tightly regulated functions in the development, regionalization, and functional differentiation of the mouse brain.

Molecular profiling indicates avian branchiomotor nuclei invade the hindbrain alar plate.

It is generally believed that the spinal cord and hindbrain consist of a motor basal plate and a sensory alar plate. We now have molecular markers for these territories. The relationship of migrating branchiomotor neurons to molecularly defined alar and basal domains was examined in the chicken embryo by mapping the expression of cadherin-7 and cadherin-6B, in comparison to genetic markers for ventrodorsal patterning (Otp, Pax6, Pax7, Nkx2.2, and Shh) and motoneuron subpopulations (Phox2b and Isl1). We show cadherin-7 is expressed in a complete radial domain occupying a lateral region of the hindbrain basal plate. The cadherin-7 domain abuts the medial border of Pax7 expression; this common limit defines, or at least approximates, the basal/alar boundary. The hindbrain branchiomotor neurons originate in the medial part of the basal plate, close to the floor plate. Their cadherin-7-positive axons grow into the alar plate and exit the hindbrain close to the corresponding afferent nerve root. The cadherin-7-positive neuronal cell bodies later translocate laterally, following this axonal trajectory, thereby passing through the cadherin-7-positive basal plate domain. Finally, the cell bodies traverse the molecularly defined basal/alar boundary and move into positions within the alar plate. After the migration has ended, the branchiomotor neurons switch expression from cadherin-7 to cadherin-6B. These findings demonstrate that a specific subset of primary motor neurons, the branchiomotor neurons, migrate into the alar plate of the chicken embryo. Consequently, the century-old concept that all primary motor neurons come to reside in the basal plate should be revised.

Selective synaptic cadherin expression by traced neurons of the chicken visual system.

The stable and specific locking-in of pre- and postsynaptic membranes in synaptogenesis may be mediated by integral membrane proteins, such as members of the cadherin family. Cadherins are ideal candidate molecules for mediating synaptic specificity because they are differentially expressed in functionally connected brain structures. We studied the expression of four classic cadherins (R-cadherin, N-cadherin, cadherin-6B and cadherin-7) at the synaptic level on the somata and the proximal neurites of identified neuron populations that were traced selectively in the developing chicken visual system. Three major findings were observed. (1) Synapses on somata of shepherd's crook cells of the optic tectum are associated preferentially with one cadherin subtype. (2) In an isthmic nucleus that contains a mixed population of cells expressing different cadherins, somatic synapses tend to express the same cadherin subtype as the rest of the cell. (3) In the oculomotor complex, two cadherin subtypes are expressed only by synapses on the axon hillock. However, another neuron type that projects from the tectum to the isthmic nucleus does not show such selective synaptic cadherin staining. Our findings support the idea that a cadherin-based adhesive mechanism can mediate synaptic specificity.

MRI atlas of the human cerebellar nuclei.

The differential role of the cerebellar cortex and nuclei has rarely been addressed in human lesion and functional brain imaging studies. One important reason is the difficulty of defining the localization of the cerebellar nuclei and extent of possible lesions based on CT or MR scans. The present MRI investigation was specifically designed to study the anatomy of the deep cerebellar nuclei. In both basal ganglia and cerebellar nuclei of healthy human subjects the amount of iron is high compared to the rest of the brain. Clusters of iron are paramagnetic and, therefore, tend to cause local inhomogenities in a magnetic field. The iron-induced susceptibility artefacts were used to visualize the cerebellar nuclei as hypointensities on MR images. A three-dimensional atlas of the dentate (D), interposed (I), and fastigial (F) nuclei is presented in standard proportional stereotaxic space coordinates based on findings in a healthy 26-year-old female. A three-dimensional axial volume of the cerebellum was acquired using a T1-weighted fast low-angle shot (FLASH) sequence on a Siemens Sonata 1.5 Tesla MR. To increase the signal to noise ratio the sequence was acquired 5 times and averaged. Each volume was registered, resampled to 1.00 x 1.00 x 1.00-mm3 voxel size and spatially normalized into a standard proportional stereotaxic space (the MNI-space) using SPM99. Localization of cerebellar nuclei were confirmed by comparison with postmortem MRI and histological microsections of another brain.

Granule cell raphes in the cerebellar cortex of chicken and mouse.

The cerebellar cortex of the chicken embryo contains parasagittal segments of Purkinje cells. At intermediate stages of development, cell-dense ribbons of migrating granule cells ("raphes") are found between the segments. The complementary pattern of granule cell raphes and Purkinje cell segments represents a basic scheme of cerebellar organization that coincides with the expression domains of various genes, such as cadherins, gene regulatory proteins, and ephrins and their receptors. We have recently found the raphe/segment pattern also in a mammalian species, the postnatal mouse. Like in the chicken, the parasagittal raphes of granule cells were observed at the boundaries of Purkinje cell segments that differentially express cadherins. The number and arrangement of the raphes in the different cerebellar lobules is roughly similar in both species. The raphe/segment pattern is thus more widely distributed in vertebrates than previously assumed.

Modularity in vertebrate brain development and evolution.

Embryonic modularity and functional modularity are two principles of brain organization. Embryonic modules are histogenetic fields that are specified by position-dependent expression of patterning genes. Within each embryonic module, secondary and higher-level pattern formation takes places during development, finally giving rise to brain nuclei and cortical layers. Defined subsets of these structures become connected by fiber tracts to form the information-processing neural circuits, which represent the functional modules of the brain. We review evidence that a group of cell adhesion molecules, the cadherins, provides an adhesive code for both types of modularity, based on a preferentially homotypic binding mechanism. Embryonic modularity is transformed into functional modularity, in part by translating early-generated positional information into an array of adhesive cues, which regulate the binding of functional neural structures distributed across the embryonic modules. Brain modularity may provide a basis for adaptability in evolution.

Expression of R-cadherin and N-cadherin by cell groups and fiber tracts in the developing mouse forebrain: relation to the formation of functional circuits.

The expression of R-cadherin and N-cadherin was mapped in the postnatal forebrain of the mouse by immunohistochemistry and in situ hybridization. Results show that the two molecules are expressed in specific and restricted patterns in numerous brain nuclei, gray matter areas and cortical layers that are widely distributed throughout the mouse forebrain at postnatal day 1. The expression pattern of R-cadherin is clearly distinct from that of N-cadherin, but overlap is observed in many areas. In many cortical areas, the two cadherins have a laminar-specific distribution that varies from region to region. In addition, immunohistochemical data revealed expression of R-cadherin protein and N-cadherin protein in the neuropil of many brain regions as well as in the axons that travel in fiber tracts such as the olfactory tract, the anterior commissure, the corpus callosum, the stria terminalis and the fornix. Often, subsets of axons within the same fiber tract differentially express R-cadherin and N-cadherin, with partial overlap of expression. The targets of the cadherin-immunoreactive fiber bundles often contain neuropil as well as cell bodies of neurons that also express the same type(s) of cadherin, suggesting that R-cadherin and N-cadherin may be involved in target recognition and the establishment of connections. Specifically, the expression of R-cadherin and N-cadherin is related to the maturation of thalamocortical sensory pathways, corticofugal pathways, and pathways associated with the hippocampal complex, the piriform cortex, and the amygdala. It is also related to the development of the cell groups associated with these pathways.Together, the results from the present study indicate the possibility that the selective adhesion of neural structures that express the same type(s) of cadherin contributes to the formation of gray matter areas, neural circuits and functional connections in the postnatal forebrain of the mouse.

Cadherin expression by embryonic divisions and derived gray matter structures in the telencephalon of the chicken.

The expression of three cadherins (cadherin-6B, cadherin-7, and R-cadherin) was studied by immunohistochemistry in the telencephalon of chicken embryos at intermediate stages of development (11 and 15 days of incubation). Expression patterns were related to cytoarchitecture and to previously published data on functional connections and on the expression of gene regulatory proteins. Our results indicate that, like in other regions of the embryonic chicken brain, the expression of each cadherin is restricted to parts of embryonic divisions as well as to particular nuclei, areas or their subdivisions. The expression patterns are largely complementary with partial overlap. The regional expression of the cadherins respects the boundary between the pallium and the subpallium as well as between various pallial and subpallial subdivisions. Novel subdivisions were found in several telencephalic areas. For example, subjacent to the hyperstriatum, the neostriatum contains multiple islands of cells with a profile of cadherin expression that differs from the surrounding matrix ("island fields"). Moreover, the expression of each cadherin is apparently associated with parts of intratelencephalic neural circuits and of thalamopallial and basal ganglia pathways. These results support a role for cadherins in the aggregation and differentiation of gray matter structures within embryonic brain divisions. The cadherin immunostaining patterns are interpreted in the context of a recently proposed divisional scheme of the avian pallium that postulates medial, dorsal, lateral, and ventral divisions as complete radial histogenetic units (Puelles et al. [2000]).

Granule cell raphes in the developing mouse cerebellum.

The cerebellar cortex of many vertebrates shows a striking parasagittal compartmentation that is thought to play a role in the establishment and maintenance of functional cerebellar connectivity. Here, we demonstrate the existence of multiple parasagittal raphes of cells in the molecular layer of the developing cerebellar cortex of postnatal mouse. The histological appearance and immunostaining profile of the raphe cells suggest that they are migrating granule cells. We therefore conclude that the granule cell raphes previously described in birds also exist in a mammalian species. The raphes in mouse are visible on nuclear stains from around birth to postnatal day 6 and are frequently found at the boundaries of Purkinje cell segments that differentially express cadherins ("early-onset" parasagittal banding pattern). A similar relation between the raphe pattern and various markers for the early-onset banding pattern has been found in the chicken cerebellum. One of the cadherins mapped in the present study (OL-protocadherin) continues to be expressed in specific Purkinje cell segments until at least postnatal day 14. At this stage of development, the borders of the OL-protocadherin-positive Purkinje cell segments coincide with the borders of Purkinje cell segments that express zebrin II, a marker for the "late-onset" parasagittal banding pattern which persists in the adult cerebellum. These findings demonstrate that the early-onset banding pattern, as reflected in the complementary arrangement of raphes/Purkinje cell segments, and the late-onset pattern of zebrin II expression share at least some positional cues during development.

R- and B-cadherin expression defines subpopulations of glial cells involved in axonal guidance in the optic nerve head of the chicken.

Glial cells play a crucial role in the organization and function of the nervous system. Cell-cell adhesion receptors of the cadherin family have been shown to participate in distinct morphogenetic processes throughout the development of the CNS, but little is known about glial expression of cadherins. Applying immunofluorescence and confocal laser scanning microscopy, we investigated R- and B-cadherin expression in relation to the glial cell differentiation in the optic nerve head and pecten oculi of developing chicken. Throughout embryonic development, R- and B-cadherin were expressed in distinct cell populations, which differentiated into distinct subtypes of glial cells. R-cadherin was located in the glia limitans perivascularis et superficialis of the optic nerve and in cells bordering the optic nerve head, where it comes in contact with the retina. B-cadherin was located in the glia limitans perivascularis et superficialis of the pecten oculi and in a subset of cells at the retinal border. R-cadherin-expressing cells differentiated unequivocally into a glial fibrillary acidic protein (GFAP)-positive but glutamine synthetase (GS)-negative phenotype, whereas B-cadherin-expressing glia developed into a GS-positive but GFAP-negative phenotype. In addition, the B-cadherin-positive population developed into a highly pigmented cell type, which was consistently associated with pecten-type capillaries. By contrast, the R-cadherin-positive glia remained unpigmented and surrounded normal brain-phenotype capillaries. These data suggest that glial cells, like neurons, may use the expression of different cadherins to segregate and differentiate into distinct subtypes, which goes hand in hand with their involvement in special functions and morphogenetic processes. To address this issue, we selectively lysed both glial subtypes in developing embryos by microinjection of R- and B-cadherin antibodies with complement. First evidence is presented for R-cadherin-positive glial cells as crucial to the organization of the optic nerve and axonal guidance at its lateral margin. B-cadherin-positive cells are involved in the axonal guidance at the pecteneal margin, avoiding the ingrowth of axons into the pecten.

N-cadherin mediates pericytic-endothelial interaction during brain angiogenesis in the chicken.

Recruitment and adhesion of pericytes to endothelial cells represents a critical step in angiogenesis. We previously demonstrated the expression of neural (N)-cadherin at contact zones between pericytes and endothelial cells in embryonic chicken brain. To elucidate N-cadherin function in early angionenesis, we injected functionally blocking antibodies on embryonic days 4 and 5 into the tectal ventricle of chicken embryos. Brains were morphologically and immunocytochemically investigated on embryonic day 6. Blocking N-cadherin function resulted in defective pericyte adhesion, increased pericyte recruitment and disturbed vascular morphogenesis. Increased pericyte recruitment did not involve elevated pericytic proliferation. Concomitant disruption of ependymal adherens junctions and of endothelial-pericytic adhesion resulted in massive hemorrhaging in the basal forebrain, in misdirected endothelial sprouting, and ectopic vascularization. Morphological investigation of control embryos on embryonic days 4 and 5 indicated the initial involvement of pericytes in stabilization of angiogenic capillary sprouts. Together these results suggest that N-cadherin mediates adhesion, recognition, and signaling between pericytes and endothelial cells required for normal vascular morphogenesis.

Formation of cadherin-expressing brain nuclei in diencephalic alar plate divisions.

During the formation of brain nuclei, the vertebrate neural tube is partitioned into distinct embryonic divisions. In this study, the expression of three members of the cadherin family of adhesion molecules (cadherin-6B, cadherin-7, and R-cadherin) was mapped to study the differentiation of gray matter in the divisions of the diencephalic alar plate of chicken embryos from embryonic day 3 (E3) to E10. At early stages of development (E3-E4), each cadherin is expressed in restricted regions of the diencephalic wall of the neural tube. The borders of some of the expression domains coincide with divisional boundaries. As the mantle layer is formed and increases in thickness from E4 to E8, morphologically discernible aggregates of cells appear that express the three cadherins differentially. These aggregates represent the anlagen of specific diencephalic brain nuclei, e.g., the lateroanterior nucleus, the ventral geniculate nucleus, the nucleus rotundus, the perirotundic area, the principal precommissural nucleus, and the lateral spiriform nucleus. Most of the cadherin-expressing diencephalic nuclei studied in this work apparently derive from a single embryonic division and remain there. The divisional boundaries are replaced gradually by the borders of cadherin-expressing brain nuclei. The current results support the idea that cadherins confer differential adhesiveness to developing structures of gray matter in the diencephalic alar plate. Moreover, they suggest that each cadherin plays a role in the formation of specific brain nuclei within the diencephalic divisions.

Morphologic fate of diencephalic prosomeres and their subdivisions revealed by mapping cadherin expression.

The expression of four cadherins (cadherin-6B, cadherin-7, R-cadherin, and N-cadherin) was mapped in the diencephalon of chicken embryos at 11 days and 15 days of incubation and was compared with Nissl stains and radial glial topology. Results showed that each cadherin is expressed in a restricted manner by a different set of embryonic divisions, brain nuclei, and their subregions. An analysis of the segmental organization based on the prosomeric model indicated that, in the mature diencephalon, each prosomere persists and forms a coherent domain of gray matter extending across the entire transverse dimension of the neural tube, from the ventricular surface to the pial surface. Moreover, the results suggest the presence of a novel set of secondary subdivisions for the dorsal thalamus (dorsal, intermediate, and ventral tiers and anteroventral subregion). They also confirm the presence of secondary subdivisions in the pretectum (commissural, juxtacommissural, and precommissural). At most of the borders between the prosomeres and their secondary subdivisions, changes in radial glial fiber density were observed. The diencephalic brain nuclei that derive from each of the subdivisions were determined. In addition, a number of previously less well-characterized gray matter regions of the diencephalon were defined in more detail based on the mapping of cadherin expression. The results demonstrate in detail how the divisions of the early embryonic diencephalon persist and transform into mature gray matter architecture during brain morphogenesis, and they support the hypothesis that cadherins play a role in this process by providing a framework of potentially adhesive specificities.

Cadherins in the central nervous system.

The central nervous system (CNS) is divided into diverse embryological and functional compartments. The early embryonic CNS consists of a series of transverse subdivisions (neuromeres) and longitudinal domains. These embryonic subdivisions represent histogenetic fields in which neurons are born and aggregate in distinct cell groups (brain nuclei and layers). Different subsets of these aggregates become selectively connected by nerve fiber tracts and, finally, by synapses, thus forming the neural circuits of the functional systems in the CNS. Recent work has shown that 30 or more members of the cadherin family of morphoregulatory molecules are differentially expressed in the developing and mature brain at almost all stages of development. In a regionally specific fashion, most cadherins studied to date are expressed by the embryonic subdivisions of the early embryonic brain, by developing brain nuclei, cortical layers and regions, and by fiber tracts, neural circuits and synapses. Each cadherin shows a unique expression pattern that is distinct from that of other cadherins. Experimental evidence suggests that cadherins contribute to CNS regionalization, morphogenesis and fiber tract formation, possibly by conferring preferentially homotypic adhesiveness (or other types of interactions) between the diverse structural elements of the CNS. Cadherin-mediated adhesive specificity may thus provide a molecular code for early embryonic CNS regionalization as well as for the development and maintenance of functional structures in the CNS, from embryonic subdivisions to brain nuclei, cortical layers and neural circuits, down to the level of individual synapses.