Biomedical subjects

Holden Higginbotham

Publications and source records attributed to Holden Higginbotham.

4 recordsLinked to original sources

PubMed2006

Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain.

The ability of the mature mammalian nervous system to continually produce neuronal precursors is of considerable importance, as manipulation of this process might one day permit the replacement of cells lost as a result of injury or disease. In mammals, the anterior subventricular zone (SVZa) region is one of the primary sites of adult neurogenesis. Here we show that doublecortin (DCX), a widely used marker for newly generated neurons, when deleted in mice results in a severe morphological defect in the rostral migratory stream and delayed neuronal migration that is independent of direction or responsiveness to Slit chemorepulsion. DCX is required for nuclear translocation and maintenance of bipolar morphology during migration of these cells. Our data identifies a critical function for DCX in the movement of newly generated neurons in the adult brain.

Active Transport, Cell Nucleus↗

PubMed2006

GSK3beta and PKCzeta function in centrosome localization and process stabilization during Slit-mediated neuronal repolarization.

In comparison with other migratory cells, neurons exhibit a unique, highly polarized morphology and a distinctive pattern of movement. This migration consists of a repeating of three distinct phases: neurite outgrowth, movement of the centrosome into the leading process, and translocation of the nucleus towards the centrosome. The direction of movement is under the control of extracellular guidance cues, but mechanisms by which these determine neuronal polarity, centrosome position, and neuronal movement are not well understood. We found that in primary olfactory bulb neuronal precursors, Slit-mediated repolarization consisted of growth of a new process from the previous trailing edge, then reorientation of the centrosome followed by nuclear translocation in the reverse direction. Inhibition of cell polarity factors GSK3beta or PKCzeta resulted in impaired centrosome reorientation and process stabilization. Our findings suggest that activation of cell polarity signaling and positioning of the centrosome ahead of the nucleus are important steps in repolarization in response to guidance cues.

Animals↗

PubMed2004

Transgenic mouse line with green-fluorescent protein-labeled Centrin 2 allows visualization of the centrosome in living cells.

The centrosome plays diverse roles throughout the cellular mitotic cycle and in post-mitotic cells. Analysis of centrosome position and dynamics in living murine cells has been limited due to a lack of adequate reporters and currently requires either cell fixation/immunostaining or transfection with centrosome reporters. Here we describe the generation and characterization of a transgenic mouse line that constitutively expresses green fluorescent protein-labeled Centrin-2 (GFP-CETN2). The phenotype of the mouse is indistinguishable from wild-type and it displays a single pair of fluorescent centrioles in cells of every organ and time point examined. This model will be helpful for visualizing the centrosome in multiple experimental conditions.

Animals↗

PubMed2004

Cortical neuronal migration mutants suggest separate but intersecting pathways.

During brain development, neurons migrate great distances from proliferative zones to generate the cortical gray matter. A series of studies has identified genes that are critical for migration and targeting of neurons to specific brain regions. These genes encode three basic groups of proteins and produce three distinct phenotypes. The first group encodes cytoskeletal molecules and produces graded and dosage-dependent effects, with a significant amount of functional redundancy. This group also appears to play important roles during the initiation and ongoing progression of neuronal movement. The second group encodes signaling molecules for which homozygous mutations lead to an inverted cortex. In addition, this group is responsible for movement of neurons through anatomic boundaries to specific cortical layers. The third group encodes enzymatic regulators of glycosylation and appears to delineate where neuronal migration will arrest. There is significant cross-talk among these different groups of molecules, suggesting possible points of pathway convergence.

Animals↗