1 UNC Neuroscience Center and , 2 Department of Cell and Molecular Physiology, The University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
Address correspondence to E.S. Anton, UNC Neuroscience Center and the Department of Cell and Molecular Physiology, The University of North Carolina School of Medicine, Rm 7109B, 103 Mason Farm Road, Chapel Hill, NC 27599-7250, USA. Email: anton{at}med.unc.edu.
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Abstract |
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Introduction |
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The integrin family of cell surface receptors is a major mediator of cellcell and cellECM interactions. Integrins can efficiently transduce signals to and from the external cell environment to the intracellular signaling and cytoskeletal compartments, while modulating signaling cascades initiated by other cellular receptors. Functional integrin receptors are formed by membrane spanning heterodimers of and ß subunits. There are at least 18
and 8 ß subunits that can form >20 different integrin receptors (Juliano, 2002
). The
subunits play a determinant role in ligand specificity and physiological response of the individual integrin receptor. ECM ligands and other cell surface molecules, such as receptor tyrosine kinases (RTKs), G-protein coupled receptors (GPCRs), growth factor receptors, L1-CAM, or members of the tetraspanin family of proteins, can bind to or associate with integrin receptors. These interactions activate, directly or indirectly, intracellular signal transduction cascades involving focal adhesion kinase (FAK), the Src family kinase fyn, MAP kinase, protein phosphatases, SH2SH3 adaptors, Rho-family GTPases and phospholipid mediators (Clark and Brugge, 1995
; Boudreau and Jones, 1999
; Giancotti and Ruoslathi, 1999; Juliano, 2002
). The activation of these signaling cascades ultimately results in a number of changes of integrin characteristics, such as spatial localization, internalization, ligand affinity, intracellular association with signaling proteins, interaction with the cytoskeleton and, finally, transcriptional modulation.
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Differential Distribution of Integrin Receptors and their Ligands in the Developing Cerebral Wall |
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Expression of integrins occurs in a continuously changing ligand environment during corticogenesis. These ligands are ECM components, such as fibronectin, tenascin, thrombospondin, glycosaminoglycans, laminins, reelin and integrin-associating molecules such as CD9 and L1-CAM (OShea et al., 1990; Sheppard et al., 1991
; Dulabon et al., 2000
; Schmid and Maness, 2001
). Laminin, though expressed primarily in the basement membrane associated with the pia matter of the cerebral cortex, is also thought to be present in the ventricular zone, subplate and marginal zone of the developing cerebral wall. Its expression along routes of migrating neurons implies that glial laminin may serve as a substratum for neuronal attachment (Liesi, 1990
; Hunter et al., 1992
). Laminin-2 (merosin), which binds to ß1 integrin and whose deficiency causes muscular dystrophy in humans, is distributed punctately on cortical neuronal processes. Fibronectin is initially found in the ventricular zone throughout the telencephalic vesicle, where it may support cell division and cell fate during neurogenesis. Eventually, fibronectin is expressed in radial glia, migrating neurons and cortical plate neurons during layer formation (Sheppard et al., 1991
, 1995
). Both laminin and fibronectin may associate with chondroitin-sulfate proteoglycans (CSPGs) and modulate neuronal adhesion (Snow et al., 1996
). CSPGs are highly expressed in the ventricular zone, preplate and preplate derivatives during cortical development. In vitro assays with thalamic neurons suggest that CSPGs may constitute barriers for neuronal migration and neurite extension, with different CSPGs functioning either as attractants or repellants (Emerling and Lander, 1996
). Secondary deficits in CSPG expression in the developing cortex in mice deficient in MARCKS (a neural substrate for protein kinase C) result in widespread neuronal ectopia in the forebrain (Blackshear et al., 1997
). Expression of both fibronectin and CSPGs declines rapidly as the cortex matures. In contrast, tenascins are not expressed in cortex until late in development, when radial glia start to differentiate into astrocytes (Sheppard et al., 1991
). The significance of the assembly of different ECM proteins in the basement membranes of the developing cortex is evident in the disrupted corticogenesis seen in mice deficient in the ECM components perlecan (Costell et al., 1999
), laminin
5 chain (Miner et al., 1998
), or laminin
1 nitrogen binding site (Halfter et al., 2002
). They are characterized by abnormal basal lamina assembly, altered radial glial development and dysplasia of neurons in the developing cortical plate. In humans, secondary deficiencies in basal lamina assembly may lead to cobblestone lissencephaly, where gaps in basal lamina enable neurons to migrate out of the developing brain to form ectopias (Buxhoeveden and Casanova, 2002
; Moore et al., 2002
; Olson and Walsh, 2002
).
Integrins are also capable of synergizing with other cell surface receptor systems in order to finely modulate a cells adhesive behavior in response to multiple environmental cues. Members of the tetra-membrane-spanning (tetraspanin) protein superfamily, including Tspan-5, CD9, CD63, CD81, CD82 and CD151, can associate with integrins and regulate their activity (Berditchevski and Odintsova, 1999; García-Frigola et al., 2001
). Low levels of CD9 are diffusely expressed in the developing brain in cell types including neuronal progenitor cells, astrocytes, microglia and oligodendroglia. CD9 associates with ß1 integrins to modulate cell motility and adhesion. CD63 is expressed on both CNS neurons and astrocytes, whereas CD81 is localized to the ependyma, choroid plexus, astrocytes and oligodendrocytes of the developing cortex (Kelic et al., 2001
). CD151 is present only at very low levels in the developing brain (Hasegawa et al., 1997
). ß1 integrins can also interact with the membrane spanning neural cell adhesion molecule L1-CAM (Silletti et al., 2000
), which is expressed on neurons in the intermediate and marginal zones and the subplate of developing cortex (Demyanenko et al., 1999
). L1integrin interactions are critical for modulation of neuronal migration during development (Thelen et al., 2002
).
The combination of distinct integrin receptor subunit expression and changing availability of types and levels of ligands may enable developing cortical neural cells to display different adhesive properties and activate different intracellular signal transduction pathways specific to particular integrinligand combinations. Distinct changes in neuronal function, shape, process extension, orientation, neuronglia interactions and glial differentiation thus generated may lead ultimately to the emergence of neuronal layers in the cerebral cortex. This is evident in the cortical phenotypes of different integrin mutants.
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Cortical Abnormalities in Mice Deficient in Integrin Subunits |
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In contrast to 3 integrin,
v integrins appear to provide optimal levels of basic cellcell adhesion needed to maintain neuronal migration and differentiation. Substantial disruption of cellular organization in cerebral wall and lateral ganglionic eminence is seen at E1112 in
v null mice. Extensive intracerebral hemorrhage in
v deficient mice, beginning at E1213, prevents further evaluation of cortical development in late surviving (until birth)
v null mice (Bader et al., 1998
).
v integrins expressed on radial glial cell surface can potentially associate with at least five different ß subunits: ß1, ß3, ß5, ß6 and ß8. Adhesive interactions involving fibronectin, vitronectin, tenascin, collagen, or laminin, ECM molecules that are found in the developing cerebral wall, can be mediated through these
v containing integrins (Moyle et al., 1991
; Hirsch et al., 1994
). Both transient cellmatrix interactions and cell anchoring mechanisms that are mediated by different
v containing integrins and their respective ligands are likely to modulate the process of glial development, neuronal translocation and differentiation in cerebral cortex.
In addition to 3 integrin, laminin isoforms in the developing cerebral cortex can also interact with
6 integrin dimers (Georges-Labouesse et al., 1998
).
6 null mice die at birth (Georges-Labouesse et al., 1996
), with abnormal laminar organization of the cerebral cortex and retina (Georges-Labouesse et al., 1998
). Chain migration of neurons in the post-natal rostral migrational stream, from the subventricular zone to the olfactory bulb, also depends on
6 integrin signaling (Jacques et al., 1998
). Analysis of
6 integrin deficient embryos revealed ectopic neuronal distribution in the cortical plate, protruding out to the pial surface. The cortical plate was further disorganized by wavy neurite outgrowth of ectopic neuroblasts. Coinciding abnormalities of laminin synthesis and deposition also occur in the mutant brain. Persistence of glial laminin throughout development may have prevented neuroblasts from appropriately arresting their migration in the developing cortical plate in
6 null mice. Since cerebral cortex still formed in
6 mutants, albeit abnormally, other integrin dimers may have overlapping functions with
6 integrins during early cortical development. The similarities in the ligand preferences of
3 and
6 integrins are suggestive of potential functional overlap. The severe and novel cortical abnormalities in
3,
6 double knock-out mutants, i.e. disorganization of cortical plate with large collection of ectopias, aberrant basal lamina organization and abnormal choroid plexus, support a synergistic role for
3 and
6 integrins during cortical development (De Arcangelis et al., 1999
). Deficiency in ß4 integrin, which only associates with
6, leads to an identical cortical phenotype. Mutations in either
6 or ß4 integrin in humans results in skin blistering (epidermolysis bullosa). However, the brain phenotype of the affected patients is unknown.
ß1 integrin in the cerebral cortex can dimerize with at least 10 different subunits, including
3,
6 and
v. Most of the cortical specific
subunits seem to dimerize only with ß1 integrin and ß1 integrin deficiency leads to lethality around E5.5 (Fassler and Meyer, 1995
; Stephens et al., 1995
). In an attempt to study the role of ß1 integrin in the developing cortex, ß1 integrin-floxed mice were crossed with nestin-cre mice, resulting in widespread inactivation of ß1 integrins in cortical neurons and glia from ~E10.5 (Graus-Porta et al., 2001
). Cortical layer formation is disrupted in these mice, in large part as a result of defective meningeal basement membrane assembly, marginal-zone formation and glial end feet anchoring at the top of the cortex. BrdU birthdating studies suggest that glial-guided neuronal migration is not significantly impaired. However, perturbed radial glial end feet development may contribute to the defective placement of neurons in the cortex. Determination of the onset of radial glial abnormalities in ß1 integrin deficient cortex (i.e. whether they occur prior to E18) and the use of quantitative bioassays for neuronradial-glia interactions may clarify whether lack of pial anchoring of radial glial cells in ß1 deficient cortex affects their ability to function concurrently as neuronal precursors and neuronal guides and contributes to the observed cortical phenotype. Furthermore, cortical neurons in ß1 deficient mice invade the marginal zone in areas devoid of reelin producing CajalRetzius (CR) cells and in regions with CR cell ectopias, accumulate underneath them. Invasion of neurons only into areas devoid of reelin producing CR cells supports a role for reelin in normal termination of neuronal migration. Since
3ß1 integrin has been shown to regulate reelin mediated detachment from glial guides, it was expected that b1 deficient neurons would continue to migrate past CR cell ectopias, instead of accumulating underneath them (Graus-Porta et al., 2001
). However, the absence of this phenotype indicates redundant functions for other known or novel reelin receptors in neuronal placement in the ß1 deficient cortex. Alternatively, since ß1 integrin is thought to modulate the gliophilicneurophilic adhesive balance in vitro (Galileo et al., 1992
; Anton et al., 1999
; Hatten, 1999
) and reelin mediated radial glial differentiation (Forster et al., 2002
), ß1 deficient neurons may have accumulated under CR cell ectopia due to an inability to regulate appropriate neuronneuron or neuronglia adhesion in response to reelin in the absence of ß1 integrin. Given the varied cortical phenotypes of
3,
6 and
v null mice and the ability of ß1 to associate with multiple other cortical
integrins, it is surprising that the ß1 conditional phenotype is not more severe. This may reflect the transdominant, transnegative, or compensatory influences distinct integrin receptor dimers exert over each other and the ECM ligands in the developing cerebral cortex. For example, an increase in fibronectin and collagen IV activity is seen in
3 null keratinocytes (Hodivala-Dilke et al., 1998
). In vitro, binding of a ligand to a signal transducing integrin can initiate a unidirectional signaling cascade affecting the function of a different target integrin in the same cell (Simon et al., 1997
; Blystone et al., 1999
). Elucidation of whether such integrin crosstalk regulates patterns of neuronal development and interactions with specific ECM molecules in the developing cortices of various integrin null mice will be informative in understanding the role of integrins in corticogenesis.
Pathways that are hypothesized to be activated downstream of integrins in developing cortical neurons include the CDK5/p35 complex and dab1. Mutant mice deficient in p35, CDK5, or dab1 exhibit major defects in laminar organization of the cerebral cortex (Feng and Walsh, 2001; Olson and Walsh, 2002
). CDK5 is a neuron-specific cyclin dependent kinase, whose activation is dependent on association with its p35 cofactor (Tsai et al., 1994
). The p35/CDK5 complex has been shown to interact with Rac, a member of the Rho family of GTPases, the Lis1-interacting protein NUDEL and the microtubule-associated protein tau (Nikolic et al., 1998
; Feng et al., 2000
; Niethammer et al., 2000
), thus providing several avenues through which it may affect cytoskeletal reorganization involved in distinct aspects of neuronal development. dab1 is a cytoplasmic adapter protein containing a PTB domain, which may interact with the NPxY motif in the cytoplasmic domains of ß1 receptors. Filamin1, a cytoskeletal protein whose mutation results in periventricular heterotopia, can also bind to ß1 and ß2 integrins (Sharma et al., 1995
; Loo et al., 1998
). Furthermore, integrin signaling can also switch distinct responses of migration modulating growth factors, such as neuregulin (NRG) (Colognato et al., 2002
). At present, the mechanisms of activation and regulation of these signaling pathways downstream of integrins during cortical development remain incompletely understood.
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Concluding Remarks |
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