The impact of TP53 activation and apoptosis in primary hereditary microcephaly.

Autosomal recessive primary microcephaly (MCPH) is a constellation of disorders that share significant brain size reduction and mild to moderate intellectual disability, which may be accompanied by a large variety of more invalidating clinical signs. Extensive neural progenitor cells (NPC) proliferation and differentiation are essential to determine brain final size. Accordingly, the 30 MCPH loci mapped so far (MCPH1-MCPH30) encode for proteins involved in microtubule and spindle organization, centriole biogenesis, nuclear envelope, DNA replication and repair, underscoring that a wide variety of cellular processes is required for sustaining NPC expansion during development.

Inhibiting microcephaly genes as alternative to microtubule targeting agents to treat brain tumors.

Medulloblastoma (MB) and gliomas are the most frequent high-grade brain tumors (HGBT) in children and adulthood, respectively. The general treatment for these tumors consists in surgery, followed by radiotherapy and chemotherapy. Despite the improvement in patient survival, these therapies are only partially effective, and many patients still die.

Goldberg-Shprintzen syndrome protein KIF1BP is a CITK interactor implicated in cytokinesis.

Goldberg-Shprintzen disease (GOSHS) is a rare microcephaly syndrome accompanied by intellectual disability, dysmorphic facial features, peripheral neuropathy and Hirschsprung disease. It is associated with recessive mutations in the gene encoding kinesin family member 1-binding protein (KIF1BP, also known as KIFBP). The encoded protein regulates axon microtubules dynamics, kinesin attachment and mitochondrial biogenesis, but it is not clear how its loss could lead to microcephaly.

CENPE Inhibition Leads to Mitotic Catastrophe and DNA Damage in Medulloblastoma Cells.

Medulloblastoma (MB) is the most frequent brain tumor in children. The standard treatment consists in surgery, followed by radiotherapy and chemotherapy. These therapies are only partially effective since many patients still die and those who survive suffer from neurological and endocrine disorders.

CITK Loss Inhibits Growth of Group 3 and Group 4 Medulloblastoma Cells and Sensitizes Them to DNA-Damaging Agents.

Medulloblastoma (MB) is the most common malignant brain tumor in children, and it is classified into four biological subgroups: WNT, Sonic Hedgehog (SHH), Group 3 and Group 4. The current treatment is surgery, followed by irradiation and chemotherapy. Unfortunately, these therapies are only partially effective.

Neuronal Cell-Intrinsic Defects in Mouse Models of Down Syndrome.

Down Syndrome (DS) is the most common genetic disorder associated with intellectual disability (ID). Excitatory neurons of DS patients and mouse models show decreased size of dendritic field and reduction of spine density. Whether these defects are caused by cell autonomous alterations or by abnormal multicellular circuitry is still unknown.

Precision Revisited: Targeting Microcephaly Kinases in Brain Tumors.

Glioblastoma multiforme and medulloblastoma are the most frequent high-grade brain tumors in adults and children, respectively. Standard therapies for these cancers are mainly based on surgical resection, radiotherapy, and chemotherapy. However, intrinsic or acquired resistance to treatment occurs almost invariably in the first case, and side effects are unacceptable in the second.

Correction to: ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly.

The authors wish to point out that the name of the first author is appearing incorrectly on Pubmed: it should be El Ghouzzi V (and not Ghouzzi VE). In addition, the words "and p53" appear at the end of the title in the original publication ( https://www.nature.

Inactivation of Citron Kinase Inhibits Medulloblastoma Progression by Inducing Apoptosis and Cell Senescence.

Medulloblastoma is the most common malignant brain tumor in children. Current treatment for medulloblastoma consists of surgery followed by irradiation of the whole neuraxis and high-dose multiagent chemotherapy, a partially effective strategy associated with highly invalidating side effects. Therefore, identification and validation of novel target molecules capable of contrasting medulloblastoma growth without disturbing brain development is needed.

Citron kinase-dependent F-actin maintenance at midbody secondary ingression sites mediates abscission.

Abscission is the final step of cytokinesis whereby the intercellular bridge (ICB) linking the two daughter cells is cut. The ICB contains a structure called the midbody, required for the recruitment and organization of the abscission machinery. Final midbody severing is mediated by formation of secondary midbody ingression sites, where the ESCRT III component CHMP4B is recruited to mediate membrane fusion.

Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly.

Mutations in citron (CIT), leading to loss or inactivation of the citron kinase protein (CITK), cause primary microcephaly in humans and rodents, associated with cytokinesis failure and apoptosis in neural progenitors. We show that CITK loss induces DNA damage accumulation and chromosomal instability in both mammals and Drosophila. CITK-deficient cells display "spontaneous" DNA damage, increased sensitivity to ionizing radiation, and defective recovery from radiation-induced DNA lesions.

ZIKA virus elicits P53 activation and genotoxic stress in human neural progenitors similar to mutations involved in severe forms of genetic microcephaly.

Epidemiological evidence from the current outbreak of Zika virus (ZIKV) and recent studies in animal models indicate a strong causal link between ZIKV and microcephaly. ZIKV infection induces cell-cycle arrest and apoptosis in proliferating neural progenitors. However, the mechanisms leading to these phenotypes are still largely obscure.

Tissue-specific control of midbody microtubule stability by Citron kinase through modulation of TUBB3 phosphorylation.

Cytokinesis, the physical separation of daughter cells at the end of cell cycle, is commonly considered a highly stereotyped phenomenon. However, in some specialized cells this process may involve specific molecular events that are still largely unknown. In mammals, loss of Citron-kinase (CIT-K) leads to massive cytokinesis failure and apoptosis only in neuronal progenitors and in male germ cells, resulting in severe microcephaly and testicular hypoplasia, but the reasons for this specificity are unknown.

West Nile virus surveillance, Guadeloupe, 2003-2004.

We conducted extensive surveillance for West Nile virus infection in equines and chickens in Guadeloupe in 2003-2004. We showed a high seroprevalence in equines in 2003 related to biome, followed by a major decrease in virus circulation in 2004. No human or equine cases were reported during the study.

Proteoglycan alterations in skin fibroblast cultures from patients affected with pseudoxanthoma elasticum.

Proteoglycans (PGs) were investigated in fibroblast cultures from both apparently normal and involved areas of skin from two patients affected with Pseudoxanthoma elasticum (PXE) and compared to control normal cells. Biochemical analysis showed that cells from the PXE-affected patients produced a PG population with stronger polyanion properties, as well as a markedly increased amount of high hydrodynamic-size PGs. Moreover, PGs from PXE-affected cells showed abnormal hydrophobic interaction properties when examined under associative conditions and included heparan sulphate (HS)-containing populations with anomalous electrophoretic mobility.

Heparin protection against Fe2+ -and Cu2+ -mediated oxidation of liposomes.

Heparin (HE) exhibited a protective effect on liposome peroxidation induced by Fe2+ and Cu2+, decreasing the formation of both conjugated dienes and thiobarbituric acid reactive substances (TBARS) in a dose-dependent manner. The antioxidant activity was more relevant in the oxidizing system employing Fe2+ and H2O2 and generating the highly reactive OH radical. The analysis of liposome size distribution by quasielastic laser light scattering showed that: (1) the native structure of the particles was completely lost after exposure to Fenton reagent; (2) the presence of HE in the reaction mixture completely prevented the peroxidative damage on liposomes.

The effect of cornea proteoglycans on liposome peroxidation.

Proteoglycans (PGs) from bovine cornea showed a protective effect on liposome peroxidation induced by Fe2+. Both chondroitin sulfate, dermatan sulfate-containing PG (CS,DS-PG) and keratan sulfate-containing PG (KS-PG) inhibited thiobarbituric acid-reactive substance formation when incubated with liposomes and Fe2+, CS,DS-PG being more effective than KS-PG. The native structure of PGs contributed markedly to antioxidant activity.

The effect of heparin on Cu(2+)-mediated oxidation of human low-density lipoproteins.

The effect of heparin (HE) on the susceptibility of human low-density lipoprotein (LDL) to Cu(2+)-induced oxidation was investigated by monitoring conjugated diene formation. HE did not modify the maximum formation of conjugated diene, but increased markedly the lag phase. The plot of change in oxidation rate vs.

Collagenase-extractable proteoglycans from lesion-free areas of human aorta.

Different proteoglycan (PG) populations were isolated from normal human aorta by extraction of minced tissue with 4M GuHCl and by further digestion of the residue with collagenase. Dissociative extraction induced a complete disappearance of Alcian Blue positive material, which was demonstrable by transmission electron microscopy before the treatment around collagen fibrils and in pericellular areas. However, 4M GuHCl extraction solubilized only an average of 60% of aorta total hexuronate content.

Modifications of proteoglycans produced by human skin fibroblast cultures during replicative senescence.

The properties of proteoglycans (PGs) produced by normal human skin fibroblasts were investigated with increasing passage. The increase of subculture number was associated with a constant increase in PG molecular size, which was particularly evident in cell layer extracts. In the cell layer, the ratio of DS-PGs/HS-PGs was markedly higher in early passage cultures.

Modifications of adhesion properties and proteoglycan structure in rat embryo fibroblast cultures with increasing passages.

Adhesion properties of rat embryo fibroblast cultures and proteoglycans (PGs) produced both in the growth medium and in the cell layer were investigated with increasing passages. Both cell-cell and cell-substrate adhesion increased with increasing subculture number. Cell adhesion properties were improved by cell treatment with chondroitinase ABC.