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The Molecular Activity and Targets of Lin28, a Developmental Timing Regulator

by
Erica L. Balzer
B.S., 2002
The College of New Jersey
Ewing, NJ

Thesis Advisor: Eric Moss, Ph.D.
Cell and Molecular Biology Program

Science Center, Room 290

Monday, August 4, 2008
10:00 AM


Abstract

For the development of any organism to occur normally, specific events must occur at the appropriate time and in order. Genes involved in controlling the timing of developmental events in C. elegans are termed heterochronic. Lin-28, a member of the heterochronic pathway, is a cytoplasmic protein with an unusual pairing of nucleic acid-binding motifs. Though its role during development has been examined genetically, little is known about how it acts molecularly. Lin-28 has homologs in many species. In mammals there are two paralogous genes, Lin28A and Lin28B. Lin28A is expressed in diverse tissues during development, including stem cells and is one of a handful of genes shown to induce the pluripotency of fibroblast cells. To determine the molecular activity and targets of Lin28A in mammals, the cellular localization, binding partners, and biological activity were assessed. Lin28A is predominately cytoplasmic with some nucleolar staining. Within the cytoplasm, Lin28A localizes to polysomes, P-bodies, and stress granules, consistent with Lin28A associating with mRNAs. In addition, Lin28A interacts with the known mRNA binding protein, PABP in a RNA dependant manner.

To identify Lin28As direct targets, its biological activity during neurogenesis was assessed. Examination of RA induced neurogenesis, showed that despite expression of Lin28A in stem cells, continued Lin28A expression does not promote the pluripotent state of embryonic carcinoma cells. Instead it causes two separable effects, an early enhancement of neurogenesis and an inhibition of gliogenesis. These two biological activities correspond to an early effect on gene expression, in which Lin28B and Igf2 expression is altered and a later inhibition of pre-let-7 processing. Examination of Lin28As two RNA binding domains found that they are differentially required for Lin-28As molecular and biological activities. Together this work indicates that Lin28A functions as a mRNA binding protein whose two RNA binding domains are differently required for Lin28As affect on neurogliogenesis. Lin28A expression is compatible with and can promote differentiation of certain lineages, while simultaneously preventing other cell fates. Importantly, it appears that Lin28A may have a role in mammals analogous to that of its C. elegans homolog in controlling transitions in successive cell fates.


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