On Directional Selectivity in Vertebrate Retina: An Experimental and Computational Study

This thesis describes an investigation of retinal directional selectivity. We show intracellular (whole-cell patch) recordings in turtle retina which indicate that this computation occurs prior to the ganglion cell, and we describe a pre-ganglionic circuit model to account for this and other findings which places the non-linear spatio-temporal filter at individual, oriented amacrine cell dendrites. The key non-linearity is provided by interactions between excitatory and inhibitory synaptic inputs onto the dendrites, and their distal tips provide directionally selective excitatory outputs onto ganglion cells. Detailed simulations of putative cells support this model, given reasonable parameter constraints. The performance of the model also suggests that this computational substructure may be relevant within the dendritic trees of CNS neurons in general.

MicroRNAs Modulate Hematopoietic Lineage Differentiation

MicroRNAs (miRNAs), an abundant class of ~22 nucleotide non-coding RNAs, are thought to play an important regulatory role in animal and plant development at the posttranscriptional level. Many miRNAs cloned from mouse bone marrow cells are differentially regulated in various hematopoietic lineages, suggesting that they might influence hematopoietic lineage differentiation. Some human miRNAs are linked to leukemias: the miR-15a/miR-16 locus is frequently deleted or down-regulated in patients with B-cell chronic lymphocytic leukemia and miR-142 is at a translocation site found in a case of aggressive B-cell leukemia. miR-181, a miRNA upregulated only in the B cell lineage of mouse bone marrow cells, promotes B cell differentiation and inhibits production of CD8⁺ T cells when expressed in hematopoietic stem/progenitor cells. In contrast miR-142s inhibits production of both CD4⁺ and CD8⁺ T cells and does not affect B cells. Collectively, these results indicate that microRNAs are components of the molecular circuitry controlling mouse hematopoiesis and suggest that other microRNAs have similar regulatory roles during other facets of vertebrate development.