Role of Mitochondria as Intracellular Shuttles for Nuclear Gene-regulatory Transcription Factors During Pluripotent Cell Division and Fate Specification

Northeastern University, Boston MA

Investigators

Abstract

In mammals, fertilization occurs through the joining of an egg and a sperm to produce a single-cell zygote. This single cell divides a few times to form a blastocyst composed of about 100 identical cells, but then a so-called cell fate decision is made: some blastocyst cells will develop into the embryo, and the others will develop into the placenta, which nourishes the developing embryo. A long-standing question in developmental biology is “What factors in the early blastocyst trigger cell-fate decision-making?” This project will explore the hypothesis that the energy-producing factories of cells, called mitochondria, guide cell-fate decisions by acting as shuttles for the delivery of factors that drive alternate cell fates. New technology will be applied to compare mitochondrial features--such as size, energy profiles, and protein makeup--in mouse embryo versus placental cells. The results are expected to shed light on key steps of cell-fate decision-making and uncover a previously unknown role for mitochondria in this process. During this research, undergraduate and graduate students will participate in innovative training activities using state-of-the-art scientific tools to forge new discoveries in biology and technology, geared towards development of a deeper understanding of how cell fate is regulated. The project also will implement an innovative team-mentorship strategy to expand opportunities for undergraduate students interested in pursuing Science, Technology, Engineering, Mathematics (STEM)-based careers to engage in research. Deciphering the core mechanisms that direct cell fate remains a high-priority research area in organ development, function, aging, and disease. The first cell fate decision in mammals, which drives formation of the inner cell mass (destined to become the embryo) and the trophectoderm (TE; destined to become the placenta), occurs during the later stages of preimplantation embryogenesis. Although several models have been offered to explain how this process is orchestrated, the identity of the actual initiating driver(s) of embryonic cell lineage specification remains unknown. One of the earliest fate-determination signals identified thus far is TEA Domain transcription factor 4 (Tead4), which activates transcription of genes required for TE identity. Supporting its critical role in cell fate specification, disruption of the Tead4 gene in mice generates morulae that fail to generate TE, resulting in embryonic lethality. With Tead4 being identified as one of the, if not the, earliest signal(s) in embryonic cell fate decision-making, it remains unclear how Tead4 function is restricted only to those cells destined to form the TE. This project will combine a technological advancement in mitochondrial subpopulation analysis with a mitochondrial lineage-tracing approach to test the hypothesis that differential allocation of mitochondrial subtypes, which differ in their biochemical properties as well as in their proteomic landscapes--including Tead4 internalization--during embryonic development drives cell lineage fate determination. By testing the significance of mitochondrial subtype heterogeneity and inter-organelle communication to TE versus ICM specification, this project will assess if mitochondrial heterogeneity guides cell fate determination, perhaps through an as-yet undiscovered role for mitochondria as transcription factor ‘shuttles’ during asymmetric cell divisions. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.