Date of Award

January 2013

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Nenad Sestan

Second Advisor

Mladen-Roko Rasin

Subject Area(s)

Neurosciences, Cellular biology, Developmental biology

Abstract

The Corticospinal (CS) tract is an efferent pathway that is responsible for the control of skilled voluntary movements, and its disruption, either during embryonic development or postnatally, imparts debilitating motor and cognitive defects or even death. Precise formation of the Corticospinal (CS) tract is a complex process, involving both intrinsic factors and external guidance cues, which is transcriptionally regulated by FEZF2 (FEZL or ZFP312), a deep layer pyramidal specific marker found in neocortical layer V neurons. However, the specific role of and interaction between FEZF2 and it's downstream targets are not yet fully understood. In our experiments, we show that FEZF2 is centrally involved in the control of a cortical layer-specific combinatorial code required for semaphorin-mediated guidance of CS axons, which leads to proper formation of CS circuitry and subsequently, fine motor behavior. Semaphorin-related axonal guidance molecules, NRP1 and PLXNA1, function as subunits of a receptor complex and their expression is under transcriptional activation of fezf2. Experiments with gain and loss of fuction and co-silencing of downstream targets of fezf2 support the feasibility of a novel developmental pathway involving the Fezf2-Nrp1/Plxna1 axis as a candidate for proper direction of subcortical projections. These findings could potentially have an impact on the better understanding of sensorimotor behavior and could further extend the scope of knowledge required for novel treatment approaches for neurological and psychiatric disorders involving the CS tract, including regeneration of severed CS tract in adulthood after an injury.

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