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Elizabeth H. Lacy: Overview

Role of Nuclear Pore Composition in Embryonic and Adult Stem Cell Differentiation

Our research on a gastrulation stage mouse mutant, mermaid (merm) identified a previously unrecognized molecular player in the regulation of stem/progenitor cell differentiation, the nuclear pore complex - NPC. The merm allele encodes a null mutation in Nup133, a nucleoporin subunit of the conserved Nup107-160 subcomplex, an essential structural unit of the NPC. Unexpectedly for a component of the Nup107-160 subcomplex, Nup133 exhibits cell-type and developmental stage-specific expression that is restricted predominantly to dividing progenitors. Lack of Nup133 impairs differentiation of pluripotent epiblast cells, as well as of ES cells, into neural progenitors competent to generate post-mitotic neurons. The Nup133-deficient neural progenitors abnormally maintain features of the transcriptional program and cell cycle of pluripotent early epiblast/ES cells. Since our studies on Nup133 deficient ES cells and embryos detected no global defects in functions normally associated with components of the NPC, nucleo-cytoplasmic transport and stability of chromosome number, Nup133 regulates stem/progenitor cell differentiation by an as yet unknown mechanism. Ongoing experiments, using both Nup133-deficient ES cells and mice carrying a Nup133 conditional allele, are guided by a working model positing that rapidly proliferating embryonic progenitor cells, as well as adult transit amplifying progenitors, require Nup133-NPCs to facilitate the alterations in gene activity and/or cell cycle parameters that direct the restriction of a cell’s differentiation potential as it commits to a lineage, sub-lineage, or terminal differentiation pathway.

Figure 1

Cell and Genetic Mechanisms Regulating Ventral Folding Morphogenesis during Mammalian Development

In amniotes ventral folding morphogenesis achieves gut internalization, linear heart tube formation, ventral body wall closure, and encasement of the fetus in extraembryonic membranes. Impairment of ventral morphogenesis results in human birth defects involving body wall, gut, and heart malformations and in mouse misplacement of head and heart. Absence of knowledge about genetic pathways and cell populations directing ventral folding in mammals has precluded systematic study of cellular mechanisms driving this vital morphogenetic process. Through tissue-specific mouse mutant analyses we identified the Bone Morphogenetic Protein (BMP) pathway as a key regulator of ventral morphogenesis. BMP2 expressed in anterior visceral endoderm (AVE) signals to epiblast derivatives during gastrulation to orchestrate initial stages of ventral morphogenesis; including foregut development and positioning of head and heart. Ongoing experiments seek to identify and characterize the target cell populations that initiate ventral folding morphogenesis in response to VE-derived BMP2.

Figure 2