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Background and Purpose: The corpus callosum serves as a bridge to associate fibres between the two cerebral hemispheres. In placental mammals, this commissure provides for higher order neurological advantages. The molecular pathways involved in the development and pathogenesis of accallosal defects are sparse. The article reviews the current progress of studies undertaken to discern the embryological and genetic basis of the development of the corpus callosum. Sources of data: The literature, including from sources such as MEDLINE and OMIM, were subjected to searches for articles reporting findings on corpus callosum development in humans and mice. Principal findings: At least forty-six malformation syndromes and metabolic disorders have been reported in patients with complete agenesis or hypoplasia (dysgenesis) of the corpus callosum. Thirteen of these syndromes have an unknown mode of genetic inheritance, and the remaining syndromes and metabolic disorders exhibit either autosomal or X-linked inheritance among affected families. The use of patients with accallosal defects have identified mutations in at least thirty genes of the human genome, and therefore with roles implicated in the development of the corpus callosum. Patients with chromosome aberrations have been useful in defining regions on chromosomes that contain candidate genes for the development of the corpus callosum. At least eighteen different human chromosomes with numerical and/or structural aberrations have been reported in patients with acallosal defects. The mouse is an excellent model to study the structural and genetic factors that influence the development of the corpus callosum, with many similarities evident in humans. Spontaneous development of acallosal defects has been reported in at least seventeen mouse strains. Furthermore, with the use of Genetically Engineered Mice, a minimum of 15 candidate callosal agenesis genes were modeled in order to provide insightful knowledge of the molecular-structural parameters required for development of the corpus callosum. Of these mice, six had complete true agenesis of the corpus callosum, five had either true agenesis or hypoplasia of the corpus callosum, and four had hypoplasia of the corpus callosum. Conclusions: The molecular mechanisms implicated in the pathogenesis of agenesis or hypoplasia of the corpus callosum are at the verge of discovery, and are challenged by the complexity of many genes involved. Despite these barriers, findings from a complementary human-mouse model system have been helpful in understanding the genetic (molecular) causes of accallosal defects, a fascinating phenotype for over a century. [ABSTRACT FROM AUTHOR]

Within the last decade, there has been sufficient evidence to support the association of epigenetic inheritance or genomic imprinting on human chromosome 14. This has been achieved with studies of imprinting on both human chromosome 14 and mouse chromosome 12, which has the largest homology to human chromosome 14. Initial studies with mouse chromosome 12 aberrations suggested that specific phenotypes due to genomic imprinting were confined to the maternal or paternal mouse chromosome 12, depending on the parent from which the chromosome was inherited. Such findings were later supplemented with human chromosome 14 aberrations that had provided evidence for imprinted intervals on this chromosome, and possibly 2 syndromes associated with a maternal or paternal uniparental disomy affecting chromosome 14. The recent discovery of 2 imprinted genes on human chromosome 14 and mouse chromosome 12 has confirmed genomic imprinting on these chromosomes. These findings will refine our understanding of the clinical consequences of human chromosome 14 aberrations and of the causes of the disease phenotype associated with defective imprinted genes. This article reviews evidence in mice and humans, and the clinical implications for genomic imprinting associated with human chromosome 14. [ABSTRACT FROM AUTHOR]

Background: Pediatric gliomas, the most common solid childhood neoplasm, manifest unique molecular signatures that distinguish them from adult gliomas. Unfortunately, most studies have focused on adult gliomas and extrapolate the findings to treat pediatric gliomas. In this study, we assessed the efficacy of Targetin, a folate conjugated analogue of Noscapine, on the treatment of pediatric low and high grade gliomas., Method: An assortment of standard cancer assays were used with different drug doses and experimental durations., Results: We found that pediatric glioma cells are more susceptible to lower doses of Targetin than parental Noscapine. Targetin functions by disrupting the microtubule network, and can likewise perturb DNA synthesis, delay the cellular transition within the S and G2M cell cycle phases, diminish anchorage independent growth and the migratory/invasiveness of pediatric glioma cells. Moreover, Targetin impairs the expression of several regulators of cancer progression belonging to prominent signalling pathways in pediatric gliomas; including Platelet Derived Growth Factor alpha and some members of the Mitogen Activated Protein Kinase cascade., Conclusion: Targetin has an excellent anti-neoplastic profile and functions to modulate the expression of several genes belonging to key cancer progression pathways in pediatric gliomas. Collectively, findings from this study highlight the usefulness of Targetin for the treatment of pediatric high and low grade gliomas.

Background: Intervention aimed at disrupting or inhibiting newly formed vascular network is highly desired to attenuate the progression of angiogenesis-dependent diseases. In cancer, this is tightly associated with the generation of VEGF by hypoxia inducible factor-1α following its activation by hypoxia. In light of the multiple cellular roles played by microtubules and their involvement in the processing of the hypoxia inducible factor-1α transcript, modulation of microtubule dynamics is emerging as a logical approach to suppress tumor reliance on angiogenesis. Targetin is a novel noscapinoid that interferes with microtubule dynamicity and inhibits the growth of cell lines from many types of cancers., Methods and Results: Utilizing in-vitro and ex-vivo angiogenic models, we discovered the vascular disrupting and anti-angiogenic properties of Targetin. Targetin disrupted pre-assembled capillary-like networks of human endothelial cells by severing cell-cell junctions, inhibiting endothelial cell proliferation and metabolic activity in the presence and absence of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Furthermore, we show that Targetin significantly inhibits the formation of neovasculature network sprouting from rat aortic explants stimulated with proangiogenic stimuli, namely VEGF or bFGF., Conclusion: We conclude that Targetin is a potential clinically promising anti-angiogenic agent for the treatment of many diseases including cancers.

Objective: holoprosencephaly is the most common forebrain malformation syndrome with a multifactorial etiology. Currently, mutations are identified in 5-10% of non syndromic, non-chromosomal cases in at least 12 genes. We report the molecular prenatal diagnosis of a fetus with alobar holoprosencephaly., Methods: CTG band karyotyping and array CGH genome-wide cytogenetic screenings were done, in conjunction with DNA sequence analyses of the SHH, ZIC2, SIX3 and TGIF genes in search of a molecular etiology and with comparison of findings to prior cases., Results: standard CTG band karyotyping and array CGH genome-wide screening failed to identify plausible chromosome imbalances or structural anomalies. However, extensive sequencing of the genomic DNA from the fetus and both parents on all exon and exon-intron boundaries of the four most commonly mutated genes: SHH, ZIC2, SIX3 and TGIF, identified codon 100 of the sonic hedgehog (SHH) gene having a hotspot for loss-of-function mutations in our case and others., Conclusion: mutations in codon 100 of SHH were discovered in both sporadic and autosomal dominant inherited cases with evidence of variable expressivity and penetrance. Collectively, this study reinforces the complexity of genotype-phenotype correlations in the prenatal diagnosis of holoprosencephalic fetuses.

The mammalian GATA family of transcription factors comprises of 6 members that are involved in diverse roles. The expression profile of GATA6 has been poorly defined in the central nervous system (CNS). In this report, we identify GATA6 expression in the normal mouse and human CNS, using Northern blot analyses, immunohistochemistry (IHC), and immunofluorescence (IF). GATA6 is expressed as a 2.2 kb transcript in the adult mouse brain and several regions of the adult human brain. Furthermore, cellular characterization demonstrates GATA6 nuclear expression in neurons, astrocytes, choroids plexus epithelium, and endothelial cells.

We previously characterized a genetically engineered mouse astrocytoma model with embryonic astrocyte-specific, activated (12)V-Ha-RAS (GFAP-RAS) transgenesis. The GFAP-RAS line Ras-B8 appears normal at birth, but 50% of mice die by 4 months from low- and high-grade astrocytomas. We examined the development and progression of astrocytomas in the Ras-B8 genetically engineered mouse. At embryonic day 16.5 (E16.5), there were no pathological differences compared to control littermates, aside from transgene expression. Diffuse astroglial hyperplasia was the first distinguishing feature in the 1-week-old Ras-B8 mice; however, these astrocytes were not transformed in vitro or in vivo. From 3 to 8 weeks the incidence of low-grade astrocytomas progressively increased with 85% of 12-week-old mice harboring low- or high-grade astrocytomas, the latter characterized by increased proliferation, nuclear atypia, and angiogenesis. Tp 53 mutations were detected in both astrocytoma grades, with high-grade astrocytomas expressing elevated levels of epidermal growth factor receptor and vascular endothelial growth factor, plus decreased levels of PTEN and p16, similar to human astrocytomas. We postulate that expression of (12)V-Ha-RAS in astroglial precursors induces astroglial hyperplasia, but transformation and subsequent progression requires additional molecular alterations resulting from aberrant activated p21-RAS. Of interest, many of these acquired alterations occur in human astrocytomas, further validating GFAP-RAS as a useful model for studying astrocytoma development and progression.