Laboratoire de Génétique et Physiopathologie des Retards Mentaux, GDPM, Institut Cochin, 24 Rue du Faubourg Saint Jacques, F-75014 Paris, , 1 INSERM U114, Collège de France, 11 Place Marcelin Berthelot, F-75231 Paris Cedex 05 and , 2 Laboratoire de Biochimie Cellulaire, CNRS UMR 7098, Université Pierre et Marie Curie, F-75252 Paris Cedex 05, France
Address correspondence to Fiona Francis, Département Génétique, Développement et Pathologie Moléculaire, CHU Cochin Port-Royal, 24 Rue du Faubourg Saint Jacques, F-75014 Paris, France. Email: francis{at}cochin.inserm.fr.
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
The strikingly similar spectrum of phenotypes in humans with either LIS1 or Doublecortin mutations suggests that these two proteins may function in the same biochemical pathway. Indeed, one report suggests that Doublecortin and LIS1 can exist in the same protein complex (Caspi et al., 2000). Detailed studies are, however, now necessary to further investigate the respective roles and relationship between these two proteins in the developing neuron. LIS1 was originally identified as a subunit of the intracellular brain form of platelet-activating factor acetylhydrolase (PAFAH) (Reiner et al., 1993
; Hattori et al., 1994
), but was later shown to also play a role in regulating microtubule dynamics (Sapir et al., 1997
). The connection between these two seemingly separate functions has not yet been clearly established. A number of recent studies have, however, shed some light on the microtubule-associated role of LIS1, emerging with a clearer hypothesis of its significance in proliferating cells and developing neurons (Gupta et al., 2002
). Several clues to the function of LIS1 were obtained from genetic studies of nuclear distribution mutants in Aspergillus nidulans (Morris, 2000
). Through these studies the homolog of LIS1, NudF, was shown to be associated in the same biochemical pathway with the heavy chain of cytoplasmic dynein (NudA) and with the NudE and NudC proteins, originally of unknown function (Aumais et al., 2001
). More recent studies have confirmed a physical interaction between LIS1 and dynein (Faulkner et al., 2000
; Liu et al., 2000
; Smith et al., 2000
), which functions as a minus end-directed microtubule-associated motor protein involved in vesicle and organelle transport (Hirokawa, 1998
). Indeed, LIS1 has been shown to regulate the function and distribution of dynein along microtubules (Gupta et al., 2002
). The evolutionary conservation of these proteins in Aspergillus, and later studies, have led to the proposal that the LIS1dynein protein complex exerts forces on the microtubules surrounding the nucleus in migrating neurons, eventually pulling this and other somal organelles into the leading process (Gupta et al., 2002
). CLIP-170, which interacts with LIS1 and possibly also dynein, may also be implicated in these mechanisms (Coquelle et al., 2002
). This nuclear migration hypothesis for the role of LIS1 is supported by the demonstration of a direct interaction between LIS1 and the mammalian NudE homologs, NUDEL and mNUDE, which co-localize at the centrosome and interact with dynein (Feng et al., 2000
; Niethammer et al., 2000
; Sasaki et al., 2000
). Interestingly, LIS1 and NUDEL co-localize predominantly at the centrosome in proliferating cells, but partially redistribute to neuronal processes during differentiation, in association with dynein (Sasaki et al., 2000
). It has thus also been proposed that the LIS1/NUDEL/dynein complex influences the transport of plus end-directed microtubules to the periphery of the migrating neuron, hence aiding the extension of the leading process (Gupta et al., 2002
). It is also possible, based on the previously described neuronal role of dynein (Hirokawa, 1998
), that LIS1 participates in the retrograde transport of vesicles and organelles, such as endosomes, from neuronal processes towards the nucleus. This data is supported by the axonal transport defects identified in Lis1 Drosophila mutants (Liu et al., 2000
). These combined data suggest that LIS1 plays a role in nuclear migration in proliferating and/or migrating cortical neurons, but suggest further dynein-related functions in migrating and/or differentiating neurons.
We and others have previously shown that Doublecortin is also a microtubule-associated protein (MAP) (Francis et al., 1999; Gleeson et al., 1999
; Horesh et al., 1999
), although as we describe here it has a number of features that distinguish it from LIS1. Firstly, Doublecortin has a much more restricted expression pattern showing no expression in proliferating cells, being limited to post-mitotic immature neuronal cells, including tangentially migrating neurons in the embryonic cortex and adult rostral migratory stream and differentiating cortical plate neurons. Secondly, in dissociated cells it has a compartmentalized subcellular localization, concentrated in the extremities of growing neurites, and does not associate with microtubules surrounding the nucleus. Thirdly, at the molecular level the predicted secondary structure of Doublecortin suggests a novel microtubule-binding domain, conserved in other brain-specific proteins of unknown function, but not found in LIS1. Fourthly, as we show here, its microtubule-associated function is likely to differ from that of the LIS1/NUDEL/dynein complex. Intriguingly, our data suggest that Doublecortin is nevertheless involved in vesicle trafficking since it interacts with the AP1 and AP2 adapter complexes (Friocourt et al., 2001
) implicated in clathrin-mediated transport to the endosomes and lysosomes and endocytosis, respectively. Our data thus suggest that Doublecortin is specifically required at the tips of growing neuronal processes, where it may play a role in the addition of membrane and/or the regulation of certain receptors or adhesion molecules implicated in cellular and possibly axonal guidance.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
We have previously shown a localization of microtubule-associated Doublecortin in growing neurites in primary cultures of mouse embryonic neurons (Francis et al., 1999). Our previous double labeling experiments showed that Doublecortin staining is most intense at the extremities of neurites and continues into the proximal regions of growth cones, but is not present in the actin-rich tips. Interestingly, a similar localization of Doublecortin has been observed in tangentially migrating neurons in explant cultures derived from the anterior sub-ventricular zone (B. Schaar and S. McConnell, personal communication). In this case Doublecortin staining was also observed at the extremities of leading processes, which thus suggests similarities in the function of this protein in differentiating cortical neurons and migrating neurons.
The subcellular localizations of LIS1 and NUDEL have been studied in detail in differentiating cortical neurons (Niethammer et al., 2000; Sasaki et al., 2000
). These experiments show a change in the distribution of NUDEL and possibly LIS1 following morphological changes as the neuron matures. In primary cortical cultures, NUDEL was predominantly localized in the soma to the region of the centrosome after 1 day in culture and was not present in the neurites, but after 3 days in culture it was also concentrated in the neurites and present in growth cones (Sasaki et al., 2000
). In order to assess the behavior of Doublecortin in comparison with these proteins we first examined its localization in very young cultures. Primary cultures were prepared from fetal mouse cerebral hemispheres at 15 days of gestation as previously described (Berwald-Netter et al., 1981
) and immunocytochemical staining was performed using anti-Dbcn pep (1:300) (Francis et al., 1999
), to detect Doublecortin and anti-
-tubulin (1:1000) (Amersham no. 356). This experiment showed that after only 16 h in culture, the predominant localization of Doublecortin is in the growing processes (Fig. 1A,B
), with little if any specific labeling observed in the soma. Indeed, no labeling of the microtubules surrounding the nucleus was observed. Double labelings with a centrosomal marker,
-tubulin, similarly showed that Doublecortin does not accumulate at the centrosome (data not shown). Doublecortin staining therefore differs from that of NUDEL since it is distributed within the very earliest growing processes in immature neurons in culture. We next examined the distribution of Doublecortin in comparison with LIS1 in 4 day old cultures. Once again the strongest Doublecortin staining was at the extremities of neurites, whereas LIS1, although present in the neurites, showed its strongest expression in the soma (data not shown). These combined data suggest that Doublecortin may play a role which differs from the function of the NUDEL/LIS1 complex in differentiating neurons.
|
Both LIS1 and NUDEL have been shown to form a complex on microtubules with the motor protein cytoplasmic dynein. Motor proteins can be characterized by their dissociation from microtubules in the presence of ATP and their association in the presence of ADP. Sasaki et al. (Sasaki et al., 2000) showed, using microtubule sedimentation assays, that both LIS1 and NUDEL could be dissociated from microtubules in the motor protein fraction in the presence of ATP. Our data suggest that Doublecortin has a different relationship with microtubules. Firstly, we have previously shown that a direct interaction occurs between Doublecortin and microtubules, not requiring other MAPs (Francis et al., 1999
). Here, the microtubule association of Doublecortin was further tested in the presence of ATP and ADP. No effect of these nucleotides was observed on the interaction of either purified Doublecortin with taxol-stabilized microtubules (Fig. 1C
) or native Doublecortin sedimented with MAP-associated microtubules (data not shown). GTP and GDP, affecting the binding of other motor proteins such as kinesin, similarly produced no changes in the Doublecortinmicrotubule complex. These studies strongly suggest a different type of microtubule association than that exhibited by the NUDEL/ LIS1/dynein proteins.
We have previously shown, nevertheless, an association between Doublecortin and other proteins involved in vesicle trafficking. Using a two-hybrid screen and in vitro and in vivo interaction studies, we identified the µ1 subunit of the AP1 adapter complex as an interacting partner of Doublecortin (Friocourt et al., 2001). Interestingly, the µ2 subunit of a highly similar complex, AP2, known to be involved in clathrinmediated endocytosis, also shows an interaction with Doublecortin (Friocourt et al., 2001
). The neuronal function of the AP1 adapter complex has not yet been examined in detail, although this complex has been shown in non-neuronal cells to be involved in clathrin-dependent protein sorting from the trans-Golgi network to the endosomes and lysosomes (Robinson and Bonifacino, 2001
). In dissociated neurons in culture we found that AP1 subunits are localized both in association with the trans-Golgi network in the soma, as expected, but also at the extremities of growing neurites, possibly associated with transported vesicles (Friocourt et al., 2001
). Thus, although our preliminary data suggest a direct association between Doublecortin and microtubules not requiring dynein, we do however observe an association with certain adapter complexes known to be implicated in transport mechanisms. The relationship between these adapter complexes and dynein now needs to be closely examined.
The Subcellular Localization in Astrocytes of a Protein Homologous to Doublecortin
We also examined the subcellular localization of the Doublecortin-like protein DCLK (Berke et al., 1998; Vreugdenhil et al., 1999
; Burgess and Reiner, 2000
; Lin et al., 2000
), a protein showing strong homology to Doublecortin. Certain isoforms of DCLK show a remarkably similar expression pattern to Doublecortin during embryonic development (Burgess and Reiner, 2000
; Lin et al., 2000
), including expression in migrating cortical neurons (Mizuguchi et al., 1999
). In addition, a number of DCLK isoforms contain a microtubule-binding domain highly homologous to that of Doublecortin, suggesting similar and perhaps connected functions (DCLK1A and 1C, Fig. 2A
). Indeed it is possible that, unlike in human, a functional redundancy of these two proteins in mouse can explain the apparently normal cortex observed in doublecortin knockout mice (Corbo et al., 2002
). Clearly, additional studies are required to further investigate the functions of DCLK. We describe here a new embryonic isoform of DCLK (DCLK1C, Fig. 2A
), which is the most closely related protein to Doublecortin identified to date. Similar to Doublecortin, this protein is 363 amino acids in length (compared to 366 amino acids for Doublecortin), is a phosphoprotein (Fig. 2B
) and has an almost identical C-terminus, unlike the other embryonic isoforms of DCLK. Interestingly, in addition to being expressed in developing mouse cortical neurons, this isoform is also expressed in astroglial cells in culture, hence showing a wider expression pattern than Doublecortin.
|
|
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
As a cortical cell begins to express neuronal markers and takes on a neuronal phenotype, it changes its morphology, extending processes to become first a migrating cell and later a differentiated neuron with axons and dendrites. Although different modes of migration exist (Nadarajah and Parnevelas, 2002), process extension is fundamental to each method. Microtubules are known to be important constituents of such processes (Baas, 1999), since they provide an architectural support and allow the transport of cargo to the extremities of the cell. Microtubule components have been extensively studied in differentiating neurons and some populations of migrating neurons, in which they are uniformly oriented in the axon and leading process (Rakic et al., 1996
), whereas in dendrites and trailing processes they exist in both orientations. Motor MAPs such as dynein play a critical role in axon and dendrite growth (and probably also leading process growth), by the transport of microtubules of a particular orientation into the processes. As the process lengthens, the microtubules become longer and are stabilized in all regions except the extremities, which remain more dynamic in order to accommodate changes in direction in response to navigational cues and to allow further growth of the process. Less stable microtubule arrays invade the growth cone in the direction of future growth. Our data showing the presence of microtubule-associated Doublecortin at the extremities of growing processes, even the earliest processes grown by neurons in culture, suggests an association of Doublecortin with less stable microtubules. In addition, it is likely that the regulation of Doublecortin by phosphorylation contributes to its compartmentalization and function in this region of the cell. A similar localization in migrating neurons (B. Schaar and S. McConnell, unpublished results) suggests a similar function of Doublecortin in migrating cells, thus influencing a mechanism in common between them. This mechanism seems likely to be the actual growth or remodeling of the neuronal process itself, in response to local environmental cues interpreted by the actin-rich tip. Defects in the ability of a cell to efficiently extend processes may be a feasible explanation for the cause of a neuronal migration disorder such as lissencephaly, characterized by the aberrant positioning of neurons.
The extension of neuronal processes depends not only on the transport of microtubules but equally importantly on the addition of membrane itself. Previous studies have shown that membrane addition in growing axons can only occur in regions containing less stable microtubules (Zakharenko and Popov, 1998), i.e. close to the growth cone. It is possible that membrane addition in leading processes occurs similarly close to the actin-rich tip, although this has not yet been formally demonstrated. The interaction between Doublecortin and adapter complexes involved in vesicle trafficking might indicate a function for Doublecortin in membrane and cargo addition to these regions. Indeed, a co-localization of Doublecortin and the AP1 complex has been demonstrated at the extremities of growing processes in both differentiating neurons in culture (Friocourt et al., 2001
) and in migrating neurons (B. Schaar and S. McConnell, unpublished results), which seems to support this hypothesis. Similar mechanisms involving the DCLK protein at the extremities of astroglial processes are also suggested by its interaction with the AP1 and AP2 complexes (Friocourt et al., 2001
). These adapter complexes, which are known to attach to membrane vesicles containing receptors and adhesion components, interact with motor MAPs allowing their transport along microtubule tracks, as demonstrated for KIF13A (Nakagawa et al., 2000
). The transport in mature neurons is bi-directional with certain motor proteins, such as the KIFs, being involved in anterograde transport (Foletti et al., 1999
) and others, such as dynein, implicated in retrograde transport. Although a direct interaction between dynein and the AP1/AP2 complex has not yet been demonstrated it seems likely that it could occur, similar to the situation with KIF13A. Although this may provide a possible link between LIS1/dynein and Doublecortin/AP1/AP2, there is as yet no evidence to suggest that Doublecortin is involved in retrograde transport. Indeed, its presence at the extremities of growing processes in developing neurons might instead suggest a potential role in the detachment of vesicles from microtubules, to allow membrane addition and, hence, process extension (Fig. 4
). Interestingly, further links to membrane proteins are suggested by the demonstration of an interaction between Doublecortin and the L1 cell adhesion molecule neurofascin (Kizhatil et al., 2002
). In this study Doublecortin was shown to interact with the phosphorylated form of the cytoplasmic domain of neurofascin, a protein showing a similar expression pattern to Doublecortin in the developing cortex and in migrating neurons of the rostral migratory stream. This confirmed interaction of Doublecortin with a membrane protein supports its potential role in dissociating membrane protein vesicles from the adapter complexes, since the presence of Doublecortin could perturb the interaction between the membrane protein and the adapter complex (Fig. 4
). By similar mechanisms, the presence of Doublecortin could potentially also regulate the endocytosis of certain membrane proteins. These hypotheses remain to be tested, in addition to the identification of the critical receptors and adhesion molecules which are sorted to the extremities of migrating and differentiating neurons. In addition to neurofascin, several candidates in migrating neurons are the Reelin receptors VLDLR and APOER2 and certain integrins (Gupta et al., 2002
).
|
![]() |
Acknowledgments |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() |
---|
Aumais JP, Tunstead JR, McNeil RS, Schaar BT, McConnell S, Lin S-H, Clark GD, Yu-Lee L-y (2001) NudC associates with Lis1 and the dynein motor at the leading pole of neurons. J Neurosci 21:17.
Baas PW (1999) Microtubules and neuronal polarity: lessons from mitosis. Neuron 22:2331.[ISI][Medline]
Berke JD, Paletzki RF, Aronsen GJ, Hyman SE, Gerfen CR (1998) A complex program of striatal gene expression induced by dopaminergic stimulation. J Neurosci 18:53015310.
Berwald-Netter Y, Martin-Moutot N, Koulakoff A, Couraud F (1981) Na+-channel-associated scorpion toxin receptor sites as probes for neuronal evolution in vivo and in vitro. Proc Natl Acad Sci USA 78:12451249.[Abstract]
Burgess HA, Reiner O (2000) Doublecortin-like kinase is associated with growth cones. Mol Cell Neurosci 16:529541.[CrossRef][ISI][Medline]
Caspi M, Atlas R, Kantor A, Sapir T, Reiner O (2000) Interaction between LIS1 and Doublecortin two lissencephaly gene products. Hum Mol Genet 9:22052213.
Chvatal A, Sykova E (2000) Glial influence on neuronal signaling. Prog Brain Res 125:199216.[ISI][Medline]
Coquelle FM, Caspi M, Cordelières FP, Dompierre JP, Dujardin DL, Koifman C, Martin P, Hoogenraad CC, Akhmanova A, Galjart N, de Mey JR, Reiner O (2002) LIS1, CLIP-170s key to the dynein/dynactin pathway. Mol Cell Biol 22:30893102.
Corbo JC, Deuel TA, Long JM, LaPorte P, Tsai E, Wynshaw-Boris A, Walsh CA (2002) Doublecortin is required in mice for lamination of the hippocampus but not the neocortex. J Neurosci 22:75487557.
Demelas L, Serra G, Conti M, Achene A, Mastropaolo C, Matsumoto N, Dudlicek LL, Mills PL, Dobyns WB, Ledbetter DH, Das S (2001) Incomplete penetrance with normal MRI in a woman with germline mutation of the DCX gene. Neurology 57:327330.
Derouiche A, Frotscher M (2001) Peripheral astrocyte processes: monitoring by selective immunostaining for the actin-binding ERM proteins. Glia 36:330341.[CrossRef][ISI][Medline]
des Portes V, Pinard JM, Billuart P, Vinet MC, Koulakoff A, Carrié A, Gelot A, Dupuis E, Motte J, Berwald-Netter Y, Catala C, Kahn A, Beldjord C, Chelly J (1998) Identification of a novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 92:5161.[ISI][Medline]
des Portes V, Souville I, Francis F, Pinard JM, Chelly J, Beldjord C, Jouk PS, Abaoub L, Joannard A (2002) So-called cryptogenic partial seizures resulting from a subtle cortical dysgenesis due to a doublecortin gene mutation. Seizure 11:273277.[CrossRef][ISI][Medline]
Faulkner NE, Dujardin DL, Tai C-Y, Vaughan KT, OConnell CB, Wang Y-L, Vallee RB (2000) A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function. Nature Cell Biol 2:784791.[CrossRef][ISI][Medline]
Feng Y, Olson EC, Stukenberg PT, Flanagan LA, Kirschner MW, Walsh CA (2000) LIS1 regulates CNS lamination by interacting with mNudE, a central component of the centrosome. Neuron 28:665679.[ISI][Medline]
Foletti DL, Prekeris R, Scheller RH (1999) Generation and maintenance of neuronal polarity: mechanisms of transport and targeting. Neuron 23:641644.[CrossRef][ISI][Medline]
Francis F, Koulakoff A, Chafey P, Vinet M-C, Schaar B, Boucher D, Reiner O, Kahn A, Denoulet P, McConnell SK, Berwald-Netter Y, Chelly J (1999) Doublecortin is a developmentally regulated, microtubule-associated protein expressed in migrating neurons. Neuron 23:247256.[ISI][Medline]
Friocourt G, Chafey P, Billuart P, Koulakoff A, Vinet M-C, Schaar BT, McConnell SK, Francis F, Chelly J (2001) Doublecortin interacts with subunits of clathrin adaptor complexes in the developing nervous system. Mol Cell Neurosci 18:307319.[CrossRef][ISI][Medline]
Gleeson JG, Allen KM, Fox JW, Lamperti ED, Berkovic S, Scheffer I, Cooper EC, Dobyns WB, Minnerath SR, Ross ME, Walsh CA (1998) doublecortin, a brain-specific gene mutated in human X-linked lissencephaly and double cortex syndrome, encodes a putative signaling protein. Cell 92:6372.[ISI][Medline]
Gleeson JG, Lin PT, Flanagan LA, Walsh CA (1999) Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 23:257271.[ISI][Medline]
Gleeson JG, Luo RF, Grant PE, Guerrini R, Huttenlocher PR, Berg MJ, Ricci S, Cusmai R, Wheless JW, Berkovic S, Scheffer I, Dobyns WB, Walsh CA (2000) Genetic and radiological heterogeneity of double cortex syndrome. Ann Neurol 47:265269.[CrossRef][ISI][Medline]
Gupta A, Tsai L-H, Wynshaw-Boris A (2002) Life is a journey: a genetic look at neocortical development. Nature Rev Genet 3:342357.[CrossRef][ISI][Medline]
Harding B (1996) Gray matter heterotopia. In: Dysplasias of cerebral cortex and epilepsy (Guerrini R, Andermann F, Canapicchi R, Roger J, Zilfkin B, Pfanner P, eds), pp. 8188. Philadelphia, PA: Lippincott-Raven.
Hattori M, Adachi H, Tsujimoto M, Arai N, Inoue K (1994) Miller Dieker lissencephaly gene encodes a subunit of brain platelet-activating factor acetylhydrolase. Nature 370:216218.[CrossRef][ISI][Medline]
Hirokawa N (1998) Kinesin and dynein superfamily proteins and the mechanism of organelle transport. Science 279:519526.
Horesh D, Sapir T, Francis F, Grayer Wolf S, Caspi M, Elbaum M, Chelly J, Reiner O (1999) Doublecortin, a stabilizer of microtubules. Hum Mol Genet 8:15991610.
Kizhatil K, Wu Y-X, Sen A, Bennett V (2002) A new activity of doublecortin in recognition of the phospho-FIGQY tyrosine in the cytoplasmic domain of neurofascin. J Neurosci 22:79487958.
Lin PT, Gleeson JG, Corbo JC, Flanagan L, Walsh CA (2000) DCAMKL1 encodes a protein kinase with homology to Doublecortin that regulates microtubule polymerization. J Neurosci 20:91529161.
Liu Z, Steward R, Luo L (2000) Drosophila Lis1 is required for neuroblast proliferation, dendritic elaboration and axonal transport. Nature Cell Biol 2:776783.[CrossRef][ISI][Medline]
Meyer G, Perez-Garcia CG, Gleeson JG (2002) Selective expression of doublecortin and LIS1 in developing human cortex suggests unique modes of neuronal movement. Cereb Cortex 12:12251236.
Mizuguchi M, Qin J, Yamada M, Ikeda K, Takashima S (1999) High expression of Doublecortin and KIAA0369 protein in fetal brain suggests their specific role in neuronal migration. Am J Pathol 155:17131721.
Morris NR (2000) Nuclear migration: from fungi to the mammalian brain. J Cell Biol 148:10971101.
Nadarajah B, Parnavelas JG (2002) Modes of neuronal migration in the developing cerebral cortex. Nature Rev Neurosci 3:423432.[ISI][Medline]
Nakagawa T, Setou M, Seog D-H, Ogasawara K, Dohmae N, Takio K, Hirokawa N (2000) A novel motor, KIF13A, transports mannose-6-phosphate receptor to plasma membrane through direct interaction with AP-1 complex. Cell 103:569581.[ISI][Medline]
Niethammer M, Smith DS, Ayala R, Peng J, Ko J, Lee M-S, Morabito M, Tsai L-H (2000) NUDEL is a novel Cdk5 substrate that associates with LIS1 and cytoplasmic dynein. Neuron 28:697711.[ISI][Medline]
Nowak L, Ascher P, Berwald-Netter Y (1987) Ionic channels in mouse astrocytes in culture. J Neurosci 7:101109.[Abstract]
Rakic P, Knyihar-Csillik E, Csillik B (1996) Polarity of microtubule assemblies during neuronal cell migration. Proc Natl Acad Sci USA 93:92189222.
Reiner O, Carrozzo R, Shen Y, Wehnert M, Faustinella F, Dobyns WB, Caskey CT, Ledbetter DH (1993) Isolation of a Miller-Dieker lissencephaly gene containing G protein -subunit-like repeats. Nature 364:717721.[CrossRef][ISI][Medline]
Robinson MS, Bonifacino JS (2001) Adaptor-related proteins. Curr Opin Cell Biol 13:444453.[CrossRef][ISI][Medline]
Sapir T, Elbaum M, Reiner O (1997) The lissencephaly 1 (LIS1) gene product interacts with tubulin and reduces microtubule catastrophe events. EMBO J 16:101108.
Sapir T, Horesh D, Caspi M, Atlas R, Burgess HA, Grayer Wolf S, Francis F, Chelly J, Elbaum M, Pietrokovski S, Reiner O (2000) Doublecortin mutations cluster in evolutionarily conserved functional domains. Hum Mol Genet 9:703712.
Sasaki S, Shionoya A, Ishida M, Gambello MJ, Yingling J, Wynshaw-Boris A, Hirotsune S (2000) A LIS1/NUDEL/cytoplasmic dynein heavy chain complex in the developing and adult nervous system. Neuron 28:681696.[ISI][Medline]
Schultz J, Milpetz F, Bork P, Ponting CP (1998) SMART, a simple modular architecture research tool: identification of signaling domains. Proc Natl Acad Sci USA 95:58575864.
Smith DS, Niethammer M, Ayala R, Zhou Y, Gambello MJ, Wynshaw-Boris A, Tsai L-H (2000) Regulation of cytoplasmic dynein behaviour and microtubule organization by mammalian Lis1. Nature Cell Biol 2:767775.[CrossRef][ISI][Medline]
Vreugdenhil E, Datson N, Engels B, de Jong, J, van Koningsbruggen S, Schaaf M, de Kloet ER (1999) Kainate-elicited seizures induce mRNA encoding a CaMK-related peptide: a putative modulator of kinase activity in rat hippocampus. J Neurobiol 39:4150.[CrossRef][ISI][Medline]
Zakharenko S, Popov S (1998) Dynamics of axonal microtubules regulate the topology of new membrane insertion into the growing neurites. J Cell Biol 143:10771086.