BranchAnalysis2D/3D automates morphometry analyses of branching structures.

Background: Morphometric analyses of biological features have become increasingly common in recent years with such analyses being subject to a large degree of observer bias, variability, and time consumption. While commercial software packages exist to perform these analyses, they are expensive, require extensive user training, and are usually dependent on the observer tracing the morphology.

New Method: To address these issues, we have developed a broadly applicable, no-cost ImageJ plugin we call 'BranchAnalysis2D/3D', to perform morphometric analyses of structures with branching morphologies, such as neuronal dendritic spines, vascular morphology, and primary cilia.

Opposing FlnA and FlnB interactions regulate RhoA activation in guiding dynamic actin stress fiber formation and cell spreading.

Filamins are a family of actin-binding proteins responsible for diverse biological functions in the context of regulating actin dynamics and vesicle trafficking. Disruption of these proteins has been implicated in multiple human developmental disorders. To investigate the roles of different filamin isoforms, we focused on FlnA and FlnB interactions in the cartilage growth plate, since mutations in both molecules cause chondrodysplasias.

Cytoskeletal proteins in cortical development and disease: actin associated proteins in periventricular heterotopia.

The actin cytoskeleton regulates many important cellular processes in the brain, including cell division and proliferation, migration, and cytokinesis and differentiation. These developmental processes can be regulated through actin dependent vesicle and organelle movement, cell signaling, and the establishment and maintenance of cell junctions and cell shape. Many of these processes are mediated by extensive and intimate interactions of actin with cellular membranes and proteins.

Filamin A mediated Big2 dependent endocytosis: From apical abscission to periventricular heterotopia.

Periventricular heterotopia (PH) is one of the most common malformations of cortical development (MCD). Nodules along the lateral ventricles of the brain, disruption of the ventricular lining, and a reduced brain size are hallmarks of this disorder. PH results in a disruption of the neuroependyma, inhibition of neural proliferation and differentiation, and altered neuronal migration.

Formin 1 and filamin B physically interact to coordinate chondrocyte proliferation and differentiation in the growth plate.

Filamin B (FlnB) is an actin-binding protein thought to transduce signals from various membrane receptors and intracellular proteins onto the actin cytoskeleton. Formin1 (Fmn1) is an actin-nucleating protein, implicated in actin assembly and intracellular signaling. Human mutations in FLNB cause several skeletal disorders associated with dwarfism and early bone fusion.

Filamin A and Big2: a shared endocytic pathway.

Neural proliferation, migration and differentiation require reorganization of the actin cytoskeleton and regulation of vesicle trafficking to provide stability in maintaining cell adhesions, allow for changes in cell shape, and establishing cell polarity. Human disorders involving the actin-binding Filamin A (FLNA) and vesicle trafficking Brefeldin-associated guanine exchange factor 2 (BIG2 is encoded by the ARFGEF2 gene) proteins are implicated in these various developmental processes, resulting in a malformation of cortical development called periventricular heterotopia (nodules along the ventricular lining) and microcephaly (small brain). Here we discuss several recent reports from our laboratory that demonstrate a shared role for both proteins in actin-associated vesicle trafficking, which is required to maintain the expression and stability of cell adhesion and cell cycle associated molecules during cortical development.

Filamin B regulates chondrocyte proliferation and differentiation through Cdk1 signaling.

Humans who harbor loss of function mutations in the actin-associated filamin B (FLNB) gene develop spondylocarpotarsal syndrome (SCT), a disorder characterized by dwarfism (delayed bone formation) and premature fusion of the vertebral, carpal and tarsal bones (premature differentiation). To better understand the cellular and molecular mechanisms governing these seemingly divergent processes, we generated and characterized FlnB knockdown ATDC5 cell lines. We found that FlnB knockdown led to reduced proliferation and enhanced differentiation in chondrocytes.

Methylphenidate and continuous spike and wave during sleep in a child with attention deficit hyperactivity disorder.

Attention-deficit/hyperactivity disorder is the most common neurobehavioral disorder in children and frequently associated with epilepsy. For patients with both conditions, methylphenidate remains a mainstay in the treatment of behavioral problems. Most studies demonstrate that methylphenidate is effective in treating children with well-controlled epilepsy, and that methylphenidate does not increase the risk of having seizures in patients with EEG abnormalities without epilepsy.

Filamin a regulates neural progenitor proliferation and cortical size through Wee1-dependent Cdk1 phosphorylation.

Cytoskeleton-associated proteins play key roles not only in regulating cell morphology and migration but also in proliferation. Mutations in the cytoskeleton-associated gene filamin A (FlnA) cause the human disorder periventricular heterotopia (PH). PH is a disorder of neural stem cell development that is characterized by disruption of progenitors along the ventricular epithelium and subsequent formation of ectopic neuronal nodules.

Seizure or syncope: lessons over time.

A 25-year-old woman with recurrent syncopal episodes presented with a first time generalized tonic clonic (GTC) seizure. She had experienced two prior fainting spells lasting seconds and associated with diet pills and dehydration. She had another similar spell prior to falling, sustaining a laceration to the right posterior occiput, and having a witnessed GTC seizure.

Periventricular Heterotopia: Shuttling of Proteins through Vesicles and Actin in Cortical Development and Disease.

During cortical development, proliferating neural progenitors exhibit polarized apical and basolateral membranes that are maintained by tightly controlled and membrane-specific vesicular trafficking pathways. Disruption of polarity through impaired delivery of proteins can alter cell fate decisions and consequent expansion of the progenitor pool, as well as impact the integrity of the neuroependymal lining. Loss of neuroependymal integrity disrupts radial glial scaffolding and alters initial neuronal migration from the ventricular zone.

Generation of neural stem cells from discarded human fetal cortical tissue.

Neural stem cells (NSCs) reside along the ventricular zone neuroepithelium during the development of the cortical plate. These early progenitors ultimately give rise to intermediate progenitors and later, the various neuronal and glial cell subtypes that form the cerebral cortex. The capacity to generate and expand human NSCs (so called neurospheres) from discarded normal fetal tissue provides a means with which to directly study the functional aspects of normal human NSC development.

Disruption of neural progenitors along the ventricular and subventricular zones in periventricular heterotopia.

Periventricular heterotopia (PH) is a disorder characterized by neuronal nodules, ectopically positioned along the lateral ventricles of the cerebral cortex. Mutations in either of two human genes, Filamin A (FLNA) or ADP-ribosylation factor guanine exchange factor 2 (ARFGEF2), cause PH (Fox et al. in 'Mutations in filamin 1 prevent migration of cerebral cortical neurons in human periventricular heterotopia'.

Insights into the gyrification of developing ferret brain by magnetic resonance imaging.

The developmental mechanisms underlying the formation of human cortical convolutions (gyri and sulci) remain largely unknown. Genetic causes of lissencephaly (literally 'smooth brain') would imply that disorders in neuronal migration cause the loss of cortical convolutions. However, prior studies have suggested that loss of sulci and gyri can also arise from impaired proliferation, disrupted lamination and loss of intracortical connections.

Periventricular nodular heterotopia and Williams syndrome.

We report here on the first case of a child with bilateral periventricular nodular heterotopia (PNH) and Williams syndrome. Fluorescent in situ hybridization (FISH) analyses demonstrated a deletion of the elastin gene in the Williams syndrome critical region (WSCR). Further mapping by loss of heterozygosity analysis both by microsatellite marker and SNP profiling demonstrated a 1.

Impaired proliferation and migration in human Miller-Dieker neural precursors.

Objective: Miller-Dieker syndrome (MDS) is a malformation of cortical development that results in lissencephaly (meaning smooth brain). This disorder is caused by heterozygous deletions on chromosome 17p13.3, including the lissencephaly 1 (LIS1) gene.

Cerebellar ataxia with progressive improvement.

Background: Nonprogressive cerebellar ataxias are characterized by a persistent, nonprogressive ataxia associated with cognitive impairment. Cerebellar hypoplasia on imaging is variable but is not predictive of the degree of ataxia or cognitive impairment.

Objective: To describe a family with a nonprogressive cerebellar ataxia associated with cognitive and motor impairments that improve with age.

Neocortical neuronal arrangement in Miller Dieker syndrome.

Miller Dieker syndrome (MDS, type I lissencephaly) is a neuronal migration disorder, which is caused by deletions along the short arm of chromosome 17 (17p13.3). Recent studies would suggest that the cortical lamination in MDS is inverted, based on morphological criteria.

Periventricular heterotopia: new insights into Ehlers-Danlos syndrome.

Nature often employs similar mechanisms to complete similar tasks, thus the evolution of homologous proteins across various organ systems to perform similar but slightly different functions. In this respect, disorders attributed to specific genetic mutations, while initially thought to be restricted in function and purpose, may provide broad insight into general cellular and molecular mechanisms of development and maintenance. One such example can be seen in the brain malformation, periventricular heterotopia (PH), which is characterized by very specific nodules of neurons that line the lateral ventricles beneath the cerebral cortex.

Etiological heterogeneity of familial periventricular heterotopia and hydrocephalus.

Periventricular heterotopia (PH) represents a neuronal migration disorder that results in gray matter nodules along the lateral ventricles beneath an otherwise normal appearing cortex. While prior reports have shown that mutations in the filamin A (FLNA) gene can cause X-linked dominant PH, an increasing number of studies suggest the existence of additional PH syndromes. Further classification of these cortical malformation syndromes associated with PH allows for determination of the causal genes.

Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex.

Disruption of human neural precursor proliferation can give rise to a small brain (microcephaly), and failure of neurons to migrate properly can lead to an abnormal arrest of cerebral cortical neurons in proliferative zones near the lateral ventricles (periventricular heterotopia). Here we show that an autosomal recessive condition characterized by microcephaly and periventricular heterotopia maps to chromosome 20 and is caused by mutations in the gene ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2). By northern-blot analysis, we found that mouse Arfgef2 mRNA levels are highest during embryonic periods of ongoing neuronal proliferation and migration, and by in situ hybridization, we found that the mRNA is widely distributed throughout the embryonic central nervous system (CNS).