Gene Expression Profiling of Seizure Disorders

Seizure disorders affect a significant percentage of the population, and researchers worldwide continue to work toward a better understanding of what initiates, propagates, and results from aberrant and excessive neuronal excitation. During the past two decades, one aspect of this research effort has been to describe the effects of seizure activity upon neuronal gene expression, with hopes of identifying the molecular mechanisms that underlie subsequent changes in cell function and survival. Here we review this body of work from the perspective of how these gene profiling efforts have evolved, starting with one-by-one analyses of specific gene targets to the more recent use of DNA microarrays to survey literally thousands of genes simultaneously. With regard to the latter, we present some of our own work that suggests that molecular mechanisms contributing to normal brain development are reiterated during seizure-induced network reorganization.     

Glia maintain follower neuron survival during Drosophila CNS development

While survival of CNS neurons appears to depend on multiple neuronal and non-neuronal factors, it remains largely unknown how neuronal survival is controlled during development. Here we show that glia regulate neuronal survival during formation of the Drosophila embryonic CNS. When glial function is impaired either by mutation of the glial cells missing gene, which transforms glia toward a neuronal fate, or by targeted genetic glial ablation, neuronal death is induced non-autonomously. Pioneer neurons, which establish the first longitudinal axon fascicles, are insensitive to glial depletion whereas the later extending follower neurons die. This differential requirement of neurons for glia is instructive in patterning and links control of cell number with axon guidance during CNS development.     

Dual nature of translational control by regulatory BC RNAs

In higher eukaryotes, increasing evidence suggests, gene expression is to a large degree controlled by RNA. Regulatory RNAs have been implicated in the management of neuronal function and plasticity in mammalian brains. However, much of the molecular-mechanistic framework that enables neuronal regulatory RNAs to control gene expression remains poorly understood. Here, we establish molecular mechanisms that underlie the regulatory capacity of neuronal BC RNAs in the translational control of gene expression. We report that regulatory BC RNAs employ a two-pronged approach in translational control. One of two distinct repression mechanisms is mediated by C-loop motifs in BC RNA 3' stem-loop domains. These C-loops bind to eIF4B and prevent the factor's interaction with 18S rRNA of the small ribosomal subunit. In the second mechanism, the central A-rich domains of BC RNAs target eIF4A, specifically inhibiting its RNA helicase activity. Thus, BC RNAs repress translation initiation in a bimodal mechanistic approach. As BC RNA functionality has evolved independently in rodent and primate lineages, our data suggest that BC RNA translational control was necessitated and implemented during mammalian phylogenetic development of complex neural systems.     

Functions and dysfunctions of mitochondrial dynamics

Recent findings have sparked renewed appreciation for the remarkably dynamic nature of mitochondria. These organelles constantly fuse and divide, and are actively transported to specific subcellular locations. These dynamic processes are essential for mammalian development, and defects lead to neurodegenerative disease. But what are the molecular mechanisms that control mitochondrial dynamics, and why are they important for mitochondrial function? We review these issues and explore how defects in mitochondrial dynamics might cause neuronal disease.     

From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function

One of the unique characteristics of higher organisms is their ability to learn and adapt to changes in their environment. This plasticity is largely a result of the brain's ability to convert transient stimuli into long-lasting alterations in neuronal structure and function. This process is complex and involves changes in receptor trafficking, local mRNA translation, protein turnover, and new gene synthesis. Here, we review how neuronal activity triggers calcium-dependent gene expression to regulate synapse development, maturation, and refinement. Interestingly, many components of the activity-dependent gene expression program are mutated in human cognitive disorders, which suggest that this program is essential for proper brain development and function.     

Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease

The kinesin, dynein, and myosin superfamily molecular motors have fundamental roles in neuronal function, plasticity, morphogenesis, and survival by transporting cargos such as synaptic vesicle precursors, neurotransmitter and neurotrophic factor receptors, and mRNAs within axons, dendrites, and synapses. Recent studies have begun to clarify the mechanisms of cargo selection and directional transport in subcellular compartments. Furthermore, molecular genetics has revealed unexpected roles for molecular motors in brain wiring, neuronal survival, neuronal plasticity, higher brain function, and control of central nervous system and peripheral nervous system development. Finally, it is also evident that molecular motors are critically involved in neuronal disease pathogenesis. Thus, molecular motor research is becoming an exciting frontier of neuroscience.     

Trekking across the brain: the journey of neuronal migration

The correct positioning of neurons during development--achieved through directed migration--is the basis for proper brain function. Several decades of research have yielded a comprehensive map illustrating the temporal and spatial events underlying neurogenesis and neuronal migration during development. The discovery of distinct migration modes and pathways has been accompanied by the identification of a large interwoven molecular network that transmits extracellular signals into the cell. Moreover, recent work has shed new light on how the cytoskeleton is regulated and coordinated at the molecular and cellular level to execute neuronal migration.     

Defining functional gene‐circuit interfaces in the mouse nervous system

Complexity in the nervous system is established by developmental genetic programs, maintained by differential genetic profiles and sculpted by experiential and environmental influence over gene expression. Determining how specific genes define neuronal phenotypes, shape circuit connectivity and regulate circuit function is essential for understanding how the brain processes information, directs behavior and adapts to changing environments. Mouse genetics has contributed greatly to current percepts of gene‐circuit interfaces in behavior, but considerable work remains. Large‐scale initiatives to map gene expression and connectivity in the brain, together with advanced techniques in molecular genetics, now allow detailed exploration of the genetic basis of nervous system function at the level of specific circuit connections. In this review, we highlight several key advances for defining the function of specific genes within a neural network .     

MNB/DYRK1A as a multiple regulator of neuronal development

MNB/DYRK1A is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family that has been strongly conserved across evolution. There are substantial data implicating MNB/DYRK1A in brain development and adult brain function, as well as in neurodegeneration and Down syndrome pathologies. Here we review our current understanding of the neurodevelopmental activity of MNB/DYRK1A. We discuss how MNB/DYRK1A fulfils several sequential roles in neuronal development and the molecular mechanisms possibly underlying these functions. We also summarize the evidence behind the hypotheses to explain how the imbalance in MNB/DYRK1A gene dosage might be implicated in the neurodevelopmental alterations associated with Down syndrome. Finally, we highlight some research directions that may help to clarify the mechanisms and functions of MNB/DYRK1A signalling in the developing brain.     

Dendrite remodeling in development and disease

One of the most important features of neuronal function is the capacity to dynamically adapt in response to changes in the environment and neuronal activity. Among cellular elements that show this kind of plasticity are dendrites, the components that receive and process neuronal inputs. Dendrite remodeling occurs during normal development of the nervous system as well as in response to injury or diseases in the adult. In either case, selective stabilization and/or elimination of dendritic branches is likely important to shape dendritic arbors. Here I review examples of the phenomena and consider potential cellular and molecular mechanisms that underlie dendrite remodeling and how they might relate in development and disease.     

The neurogenetics of sexually dimorphic behaviors from a postdevelopmental perspective

Most sexually reproducing animal species are characterized by two morphologically and behaviorally distinct sexes. The genetic, molecular and cellular processes that produce sexual dimorphisms are phylogenetically diverse, though in most cases they are thought to occur early in development. In some species, however, sexual dimorphisms are manifested after development is complete, suggesting the intriguing hypothesis that sex, more generally, might be considered a continuous trait that is influenced by both developmental and postdevelopmental processes. Here, we explore how biological sex is defined at the genetic, neuronal and behavioral levels, its effects on neuronal development and function, and how it might lead to sexually dimorphic behavioral traits in health and disease. We also propose a unifying framework for understanding neuronal and behavioral sexual dimorphisms in the context of both developmental and postdevelopmental, physiological timescales. Together, these two temporally separate processes might drive sex‐specific neuronal functions in sexually mature adults, particularly as it pertains to behavior in health and disease.