The lissencephaly gene product Lis1, a protein involved in neuronal migration, interacts with a nuclear movement protein, NudC

Important clues to how the mammalian cerebral cortex develops are provided by the analysis of genetic diseases that cause cortical malformations [1-5]. People with Miller-Dieker syndrome (MDS) or isolated lissencephaly sequence (ILS) have a hemizygous deletion or mutation in the LIS1 gene [3,6]; both conditions are characterized by a smooth cerebral surface, a thickened cortex with four abnormal layers, and misplaced neurons [7,8]. LIS1 is highly expressed in the ventricular zone and the cortical plate [9,10], and its product, Lis1, has seven WD repeats [3]; several proteins with such repeats have been shown to interact with other polypeptides, giving rise to multiprotein complexes [11]. Lis1 copurifies with platelet-activating factor acetylhydrolase subunits alpha 1 and alpha 2 [12], and with tubulin; it also reduces microtubule catastrophe events in vitro [13]. We used a yeast two-hybrid screen to isolate new Lis1-interacting proteins and found a mammalian ortholog of NudC, a protein required for nuclear movement in Aspergillus nidulans [14]. The specificity of the mammalian NudC-Lis1 interaction was demonstrated by protein-protein interaction assays in vitro and by co-immunoprecipitation from mouse brain extracts. In addition, the murine mNudC and mLis1 genes are coexpressed in the ventricular zone of the forebrain and in the cortical plate. The interaction of Lis1 with NudC, in conjunction with the MDS and ILS phenotypes, raises the possibility that nuclear movement in the ventricular zone is tied to the specification of neuronal fates and thus to cortical architecture.     

X-linked female band heterotopia-male lissencephaly syndrome

OBJECTIVE: The purpose of this study was to determine if a small pneumothorax would influence the pleurodesis resulting from talc instillation. METHODS: Sixty rabbits received an intrapleural injection of 400 mg/kg talc slurry. One half also received 10 mL of air intrapleurally after the talc. Ten rabbits in each group were killed 2, 14, and 28 days after instillation. RESULTS: Two days after the injection, the mean volume of air in the animals that had received the air was 7.5+/-0.4 mL. There was no air present in any other rabbits. The volume of pleural fluid and the pleural fluid glucose, protein, cell count, and differential were similar in both groups on day 2, while the LDH level was significantly higher in the air group (p<0.05). The degree of gross adhesions and microscopic fibrosis was similar in both groups and increased with time. CONCLUSIONS: A small pneumothorax does not decrease the efficacy of talc pleurodesis in our experimental model. These results suggest that the presence of a small amount of intrapleural air is not a contraindication to talc pleurodesis in humans.     

Prenatal diagnosis and management of fetal hydrocephaly and lissencephaly

Two cases of prenatal diagnosis of lissencephaly are presented in the context of a series of 118 cases of prenatally diagnosed hydrocephalus. Within this series there was one case of Walker-Warburg syndrome and another of Miller-Dieker syndrome. It is stressed that the cases reported here of ventriculomegaly diagnosed in utero show a very different outcome from those in published studies of fetal hydrocephalus which only deal with patients in whom the diagnosis was determined after birth. In those postnatal series there is a considerable selection bias, and the fate of the fetuses reported here was much worse than in postnatal series. Of the 118 fetuses 6 had fetal infections, 6 had chromosomal abnormalities, 26 had associated spina bifida, 64 fetuses had associated other anomalies, and only 28 had isolated hydrocephalus. Although it is difficult to determine the prognosis individually after prenatal diagnosis of ventriculomegaly, the data presented here may be helpful in counseling parents prenatally. The counseling should be performed with the collaboration of obstetricians, pediatricians, surgeons, and geneticists.     

New insights into the genetics of lissencephaly

The cause of chronic inflammatory bowel disease remains unknown. A genetic origin has been suggested by studies in twins. The gene or genes involved in Crohn's disease is probably situated on chromosome 16 and the genes involved in ulcerative colitis on chromosomes 2 and 7. It will undoubtedly take some time before the exact loci are precisely identified, but current research suggests that clinical applications are not far off.     

Subcortical laminal heterotopia and lissencephaly: cerebral malformations of X-linked inheritance

The effects of single and repeated administration of amphetamine (5 mg/kg, i.p., twice a day for 14 days) on the thyrotropin-releasing hormone (TRH) level, release and receptors in the rat striatum and nucleus accumbens were evaluated. Both treatments decreased the TRH level in those structures at 2 h after the drug injection. These effects were accompanied with elevation of the basal release of TRH from the nucleus accumbens and striatal slices at the same time point, whereas the stimulated (K+, 56 mM) TRH release was attenuated following repeated amphetamine administration. Acute amphetamine had no effect on the density and affinity of TRH receptors. Repeated amphetamine increased the Bmax of TRH receptors in the striatum (by ca 49%) and nucleus accumbens (by ca 38%) at 2 h after the last drug injection. At 72 h after the last amphetamine administration, the Bmax of the TRH receptor in the striatum was still elevated (by ca 42%), whereas in the nucleus accumbens it returned to control level. No changes in the affinity of TRH receptors following repeated amphetamine were found. The obtained results indicate that repeated amphetamine evokes long- and short-term up-regulation of TRH receptors in the rat striatum and nucleus accumbens, respectively. Furthermore, it is suggested that these changes may be an adaptive response to the amphetamine-induced alterations in the TRH tissue level and release.     

Lens epithelial cell proliferation, migration, and metaplasia following capsulorhexis

AIM: To study the behaviour of residual lens epithelial cells after capsulorhexis and expression of material from the isolated lens. METHODS: Human and bovine lens capsules were isolated, sterile non-toxic silicone rings inserted, and the preparations placed in organ culture for up to 12 weeks. Cell coverage of the posterior lens capsule was recorded and the capsules were examined, both pre- and post-coverage, for (a) proliferative activity and (b) cytoskeletal components. RESULTS: After a lag period outgrowth was observed across the posterior capsule. The rate of cell coverage was dependent upon both species and the presence or absence of serum. The proliferative activity of the cells was greatest at or near the leading edge and decreased once covered. Wrinkles became visible in the posterior capsule during the late stages of precoverage and increased in both number and complexity. All cells on both the human and bovine posterior capsules contained F-actin and vimentin and the majority were immunolabelled for alpha-smooth muscle actin (alpha-SMA). CONCLUSIONS: This model exhibits many of the in vivo characteristics of the lens capsule after extracapsular surgery and may prove useful in further elucidating the cellular mechanisms of posterior capsule opacification.     

Neutrophil migration, oxidative metabolism, and adhesion in elderly and young subjects

OBJECTIVE: To evaluate neutrophil functions in the elderly. METHODS: We investigated the PMN migration in vivo and PMN superoxide production and adhesion in response to a variety of compounds; PMN have been isolated both from blood and from a skin experimental exudate (obtained by Senn's skin window technique) of 25 normal elderly and of 25 normal young control subjects. RESULTS: No difference was found in PMN migration in vivo (62.9 +/- 21.3 x 10(6) and 65.5 +/- 9.1 x 10(6) PMN/cm2/24 hours in elderly and young subjects respectively), neither were different the adhesion under basal condition and after some stimuli and the superoxide production in basal condition and in response to STZ and PMA in two groups. In elderly subjects superoxide production, in response to fMLP, markedly resulted lower than in young controls both by circulating PMNs (3.6 +/- 2.7 and 9.3 +/- 3.3 nMOLES O2-/10(6) PMN respectively, p < 0.0001) and by exudate PMNs (13.6 +/- 4.3 and 19.4 +/- 6 nMOLES O2-/10(6) PMNs respectively, p < 0.005). CONCLUSION: Many PMN functions in the elderly do not differ from young people, suggesting that the overall defense function of these cells is not affected by aging. The only parameter that we have found to be different between the two groups is the poor superoxide production after fMLP stimulus of PMNs. The stimulus- and function-specificity of this defect in PMNs from elderly subjects indicates the existence of a dysregulation of the signal transduction pathway distal to fMLP receptor and proximal to NADPH oxidase activation.     

Role of intermediate filaments in migration, invasion and metastasis

The expression of intermediate filament proteins is remarkably tissue-specific which suggests that the intermediate filament (IF) type(s) present in cells is somehow related to their biological function. However, in some cancers-particularly malignant melanoma and breast carcinoma, there is a strong indication that vimentin and keratin IFs are coexpressed, thus presenting as a dedifferentiated or interconverted (between epithelial and mesenchymal) phenotype. In this review, two in vitro models are presented which recapitulate the interconverted phenotype in human melanoma and breast carcinoma, and allow, for the first time, unique observations to be made with respect to the role of IFs in cancer progression. These studies have provided direct evidence linking overexpression of keratin IFs in human melanoma with increased migratory and invasive activity in vitro, which can be down-regulated by substituting dominant-negative keratin mutants. Overexpression of vimentin IFs in the breast carcinoma model leads to augmentation of motility and invasiveness in vitro, which can be transiently down-regulated by treatment with antisense oligonucleotides to vimentin. Additional experimental evidence suggests that the mechanism(s) responsible for the differential expression of metastatic properties associated with the interconverted phenotype rest(s) in the unique interaction, either direct or indirect, of IFs with specific integrins interacting with the extracellular matrix. In this review, we discuss the observations derived from the human melanoma and breast carcinoma models to address the hypothesis that the ability to coexpress vimentin and keratins confers a selective advantage to tumor cells in their interpretation of and response to signaling cues from the extracellular matrix. The ramifications of these observations are discussed with respect to the patholophysiology of the respective in situ tumors.     

Climate, economy, and the differential migration of white and nonwhite workers.

Studied migration into each of the 48 continental United States between 1950 and 1960 for 20-44 yr. old whites and nonwhites as it related to climate and economic variables within those states during the same period. For whites, a better climate in the form of more sunshine and higher minimum temperatures was about equally predictive of immigration as were average weekly earnings and increased employment rates. For nonwhites, increased employment rates, weekly earnings, as well as amount of public assistance payments were highly predictive of immigration. Good climate was negatively associated with nonwhite immigration. The 8 predictor variables used (5 climatic and 3 economic) accounted for 46.9% of the white and 64.8% of the nonwhite variance into the 48 states. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Natural killer cells: endothelial interactions, migration, and target cell recognition

Our previous studies with mice showed that chronic ethanol (EtOH) administration affected the incorporation of unsaturated free fatty acids (FFA) into four major brain phospholipids (PL). In the current study, we investigated the effects of ganglioside GM1 pretreatment on EtOH-induced changes in the incorporation of various FFA into cerebral PL in mice. Consistent with our earlier findings, the results suggest that chronic EtOH exposure alters the incorporation of unsaturated fatty acids into phosphatidylinositol (PI), phosphatidylserine, and phosphatidylcholine (PC), but not into phosphatidylethanolamine (PE). No significant differences were observed with stearic acid. The ganglioside GM1 treatment led to increased incorporation of linoleic acid (LA) into PE and PC and appeared to enhance the EtOH-produced effects especially for docosahexaenoic acid (DHA) and to a lesser extent for oleic acid, LA, and arachidonic acid, when compared to the untreated control group. However, when comparison was made with the EtOH-alone group, significant differences were observed only with DHA incorporation and mainly into PE and PI. Thus acyltransferases may play an important role in membrane adaptation to the injurious effects of EtOH and GM1 appears to enhance selective incorporation of FFA into membrane PL; a process that may represent a repair mechanism.     

Protein-tyrosine phosphatase Shp-2 regulates cell spreading, migration, and focal adhesion

Shp-2, a widely expressed cytoplasmic tyrosine phosphatase with two SH2 domains, is believed to participate in signal relay downstream of growth factor receptors. We show here that this phosphatase also plays an important role in the control of cell spreading, migration, and cytoskeletal architecture. Fibroblast cells lacking a functional Shp-2 were impaired in their ability to spread and migrate on fibronectin compared with wild-type cells. Furthermore, Shp-2 mutant cells displayed an increased number of focal adhesions and condensed F-actin aggregation at the cell periphery, properties reminiscent of focal adhesion kinase (FAK)-deficient cells. This is consistent with our previous observations in vivo that mice homozygous for the Shp-2 mutation died at midgestation with similar phenotype to FAK and fibronectin-deficient embryos, having severe defects in mesodermal patterning, particularly the truncation of posterior structures. Biochemical analysis demonstrated that FAK dephosphorylation was significantly reduced in Shp-2 mutant cells in suspension. Furthermore, regulated association of Src SH2 domain with FAK and paxillin during cell attachment and detachment on fibronectin was disrupted in Shp-2 mutant cells. This report defines a unique role of the Shp-2 tyrosine phosphatase in cell motility, which might guide the design of a new strategy for pharmaceutical interference of tumor metastasis.     

Alteration of the LIS1 gene in Japanese patients with isolated lissencephaly sequence or Miller-Dieker syndrome

Maffucci's syndrome is a rare, congenital disease due to neuro-ectodermal dysplasia and is characterized by enchondromatosis and multiple soft tissue haemangiomata. A case of Maffucci's syndrome with haemangiomata along the upper airways requiring laser surgery is described. The literature on Maffucci's syndrome is reviewed.