Identification and functional characterization of two patterning genes, Zic4 and Ten_m3, in topographic map formation of the visual pathway

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, February 2010.Cataloged from PDF version of thesis.Includes bibliographical references (p. 114-123).A central feature of visual pathway development is its organization into retinotopic maps. The developmental process by which these maps form involves a transition from early patterning cues to arrays of axonal guidance factors allowing the relative order of retinotopic axons to be preserved. Mechanisms linking patterning molecules of early development to topographic wiring and subsequent functional responses are not well understood. In this thesis, I performed a microarray screen comparing gene expression in early visual and auditory regions of the thalamus in order to identify early patterning candidates with a potential role in visual pathway differentiation. Among the candidates enriched in the visual thalamus, the transcription factor, Zic4, was found to be expressed in gradients of the developing retina, lateral geniculate nucleus (LGN) and primary visual cortex (V 1). Mice lacking Zic4 exhibited a deficit in eye-specific patterning to the thalamus that was complementary to the phenotype seen in mice lacking Tenm3, a type II homophilic transmembrane receptor and transcriptional regulator. Using intrinsic signal optical imaging techniques, I characterized the functional properties of primary visual cortical retinotopic maps in Zic4 and Ten_m3 null mice and identified complementary changes in the ipsilateral representation of V1, as well as evidence for eye-specific mismatch in the cortical binocular zone. Additionally, complementary positional shifts in VI were found in these mutants identifying a bidirectional modulation of mapping mechanisms in the visual pathway.(cont.) In order to test whether Zic4 and Ten_m3 interact in serial or parallel pathways, I analyzed the retinogeniculate and cortical maps in the combination mutant. The Ten_m3/Zic4 double null mouse exhibited a partial rescue of retinogeniculate mapping and a complete reversal of the cortical changes found in either mutant alone, suggesting that the two genes interact to modulate common downstream effectors in opposite directions. In sum, this thesis presents a gene microarray screen used to identify Zic4 as a novel visual patterning gene, characterizes its loss-of-function phenotype on retinotopic mapping in the thalamus and cortex, and studies its antagonistic interaction with Ten_m3, another visual pathway patterning gene with a complementary loss-of-function phenotype.by Sam H. Horng.Ph.D

The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination

Growth factors of the gp130 family promote oligodendrocyte differentiation, and viability, and myelination, but their mechanisms of action are incompletely understood. Here, we show that these effects are coordinated, in part, by the transcriptional activator Krüppel-like factor-6 (Klf6). Klf6 is rapidly induced in oligodendrocyte progenitors (OLP) by gp130 factors, and promotes differentiation. Conversely, in mice with lineage-selective Klf6 inactivation, OLP undergo maturation arrest followed by apoptosis, and CNS myelination fails. Overlapping transcriptional and chromatin occupancy analyses place Klf6 at the nexus of a novel gp130-Klf-importin axis, which promotes differentiation and viability in part via control of nuclear trafficking. Klf6 acts as a gp130-sensitive transactivator of the nuclear import factor importin-α5 (Impα5), and interfering with this mechanism interrupts step-wise differentiation. Underscoring the significance of this axis in vivo, mice with conditional inactivation of gp130 signaling display defective Klf6 and Impα5 expression, OLP maturation arrest and apoptosis, and failure of CNS myelination

Vocal Communication Between Male Xenopus Laevis

This study focuses on the role of male - male vocal communication in the reproductive repertoire of the South African clawed frog, Xenopus laevis. Six male and two female call types were recorded from native ponds in the environs of Cape Town, South Africa. These include all call types previously recorded in the laboratory as well as one previously unidentified male call: chirping. The amount of calling and the number of call types increased as the breeding season progressed. Laboratory recordings indicated that all six male call types were directed to males; three of these were directed to both sexes and three were directed exclusively to males. Both female call types were directed exclusively to males. The predominant call type, in both field and laboratory recordings, was the male advertisement call. Sexual state affected male vocal behaviour. Male pairs in which at least one male was sexually active (gonadotropin injected) produced all call types, whereas pairs of uninjected males rarely called. Some call types were strongly associated with a specific behaviour and others were not. Clasped males always growled and clasping males typically produced amplectant calls or chirps; males not engaged in clasping most frequently advertised. The amount of advertising produced by one male was profoundly affected by the presence of another male. Pairing two sexually active males resulted in suppression of advertisement calling in one; suppression was released when males were isolated after pairing. Vocal dominance was achieved even in the absence of physical contact (clasping). We suggest that X. laevis males gain a reproductive advantage by competing for advertisement privileges and by vocally suppressing neighbouring males

Erratum to: Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (Autophagy, 12, 1, 1-222, 10.1080/15548627.2015.1100356

non present