Fat cells (adipocytes) develop from adipocyte precursor cells (preadipocytes) that themselves derive from mesenchymal progenitors. Although the events controlling preadipocyte differentiation into mature adipocytes have been largely explored, the mechanisms that direct mesenchymal progenitors down the adipocyte pathway remain unknown. Similarly, although adipocytes are generally thought to derive from mesoderm, key information is lacking regarding the origin and the development of the adipose tissue during embryogenesis. The aim of this study was to gain insight into the ontogeny of fat cells, both in mouse embryonic stem (mES) cell-derived cultures and during normal development. We first used genetically engineered mES cells to produce and select ES cellderived neuroepithelial progenitors and showed that neuroectoderm, rather than mesoderm, may be a source of adipocytes in mES cell-derived cultures. We then used primary and secondary cultures of developing quail neural crest (NC) cells to demonstrate that NC cells are able, upon stimulation with defined factors, to differentiate into adipocytes, thus providing a powerful system to study the earliest stages of adipocyte differentiation. Finally, we mapped NC derivatives in vivo using Cre-mediated recombination in transgenic mice and demonstrated that a subset of adipocytes originates from the NC during normal development.
Addition of nerve growth factor (NGF) to PC12 cells promotes neuronal di erentiation while inhibiting cell proliferation. In order to understand how NGF exerts its antimitogenic e ect during di erentiation, we have studied the mechanism by which this factor activates the promoter of the CDK inhibitor p21 WAF1/CIP1 . The minimal region of the p21 promoter required for the NGF-induction was mapped to a contiguous stretch of 10 bp located 83 bases upstream of the transcription initiation site. This GC-rich region was shown to interact speci®cally with the transcription factor Sp1 and the related protein Sp3, in either exponentiallygrowing or NGF-treated PC12 cells. The addition of NGF resulted in an accumulation of the transcriptional co-activator p300 in complexes associated with the NGF-responsive region. Transcriptional activity of Sp1, Sp3 and p300 was speci®cally induced by NGF in a Gal4-fusion assay, indicating that induction of p21 during neuronal di erentiation may involve regulation of the activity of these factors by NGF. Furthermore, p300 was able to act as a co-activator for Sp1-mediated transcriptional activation in PC12 cells, suggesting that p300 and Sp1 may cooperate in activating p21 transcription during the withdrawal of neuronal precursors from the cell cycle. This hypothesis is supported by experiments showing that p300 and Sp1 form complexes in PC12 cells.
The timing of oligodendrocyte development is regulated by thyroid hormone (TH) in vitro and in vivo, but it is still uncertain which TH receptors mediate this regulation. TH acts through nuclear receptors that are encoded by two genes, TRa and TRb. Here, we provide direct evidence for the involvement of the TRa1 receptor isoform in vivo, by showing that the number of oligodendrocytes in the postnatal day 7 (P7) and P14 optic nerve of TRa1±/± mice is decreased compared with normal. We demonstrate that TRa1 mediates the normal differentiation-promoting effect of TH on oligodendrocyte precursor cells (OPCs): unlike wild-type OPCs, postnatal TRa1±/± OPCs fail to stop dividing and differentiate in response to TH in culture. We also show that overexpression of TRa1 accelerates oligodendrocyte differentiation in culture, suggesting that the level of TRa1 expression is normally limiting for TH-dependent OPC differentiation. Finally, we provide evidence that the inhibitory isoforms of TRa are unlikely to play a part in the timing of OPC differentiation.
The current epidemic of obesity and overweight has caused a surge of interest in the study of adipose tissue formation. Much progress has been made in defining the transcriptional networks controlling the terminal differentiation of adipocyte progenitors into mature adipocytes. However, the early steps of adipocyte development and the embryonic origin of this lineage have been largely disregarded until recently. In mammals, two functionally different types of adipose tissues coexist, which are both involved in energy balance but assume opposite functions. White adipose tissue (WAT) stores energy, while brown adipose tissue (BAT) is specialized in energy expenditure. WAT and BAT can be found as several depots located in various sites of the body. Individual fat depots exhibit different timing of appearance during development, as well as distinct functional properties, suggesting possible differences in their developmental origin. This hypothesis has recently been revisited through large-scale genomics studies and in vivo lineage tracing approaches, which are reviewed in this report. These studies have provided novel fundamental insights into adipocyte biology, pointing out distinct developmental origins for WAT and BAT, as well as for individual WAT depots. They suggest that the adipose tissue is composed of distinct mini-organs, exhibiting developmental and functional differences, as well as variable contribution to obesity-related metabolic diseases.
combinations of known signal molecules to promote the development of OPCs from selected, ES-cell-derived, neuroepithelial cells. We show that the earliest stages of oligodendrocyte development follow an ordered sequence that is remarkably similar to that observed in vivo, suggesting that the ES-cell-derived neuroepithelial cells follow a normal developmental pathway to produce oligodendrocytes. These engineered ES cells thus provide a powerful system to study both the mechanisms that direct CNS stem cells down the oligodendrocyte pathway and those that influence subsequent oligodendrocyte differentiation. This strategy may also be useful for producing human cells for therapy and drug screening.
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