Biomedical subjects

Jesse J Lugus

Publications and source records attributed to Jesse J Lugus.

4 recordsLinked to original sources

PubMed2006

GATA2 functions at multiple steps in hemangioblast development and differentiation.

Molecular mechanisms that regulate the generation of hematopoietic and endothelial cells from mesoderm are poorly understood. To define the underlying mechanisms, we compared gene expression profiles between embryonic stem (ES) cell-derived hemangioblasts (Blast-Colony-Forming Cells, BL-CFCs) and their differentiated progeny, Blast cells. Bioinformatic analysis indicated that BL-CFCs resembled other stem cell populations. A role for Gata2, one of the BL-CFC-enriched transcripts, was further characterized by utilizing the in vitro model of ES cell differentiation. Our studies revealed that Gata2 was a direct target of BMP4 and that enforced GATA2 expression upregulated Bmp4, Flk1 and Scl. Conditional GATA2 induction resulted in a temporal-sensitive increase in hemangioblast generation, precocious commitment to erythroid fate, and increased endothelial cell generation. GATA2 additionally conferred a proliferative signal to primitive erythroid progenitors. Collectively, we provide compelling evidence that GATA2 plays specific, contextual roles in the generation of Flk-1+ mesoderm, the Flk-1+Scl+ hemangioblast, primitive erythroid and endothelial cells.

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PubMed2005

Stepwise commitment from embryonic stem to hematopoietic and endothelial cells.

There is great excitement in generating different types of somatic cells from in vitro differentiated embryonic stem (ES) cells, because they can potentially be utilized for therapies for human diseases for which there are currently no effective treatments. Successful generation and application of ES-derived somatic cells requires better understanding of molecular mechanisms that regulate self-renewal and lineage commitment. Accordingly, many studies are aimed toward understanding mechanisms for maintaining the stem cell state and pathways leading to lineage specification. In this chapter we discuss recent studies that examine molecules that are critical for ES cell self-renewal, as well as hematopoietic and endothelial cell lineage differentiation from ES cells.

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PubMed2005

Developmental relationship between hematopoietic and endothelial cells.

Blood (hematopoietic cells) and blood vessels (endothelial cells) develop from mesoderm via a transitional progenitor known as the hemangioblast. Flk-1, a receptor tyrosine kinase, and Scl, a basic helix-loop-helix transcription factor, are two critical molecules functioning in this process. Recent studies have shown that Flk-1 expressing mesoderm contributes to the circulatory system, including hematopoietic, endothelial, smooth muscle, skeletal muscle, and cardiac muscle cells. Our studies suggest that hemangioblast specification within Flk-1 expressing mesoderm is regulated by Scl expression. Herein, we review studies that have utilized transgenic mouse models as well as an in vitro model of embryonic stem cell differentiation, both of which have greatly contributed to the current understanding of the cellular and molecular pathways regulating hemangioblast development and differentiation.

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PubMed2003

Cloning of wrinkle-free, a previously uncharacterized mouse mutation, reveals crucial roles for fatty acid transport protein 4 in skin and hair development.

Wrinkle-free (wrfr) is a previously uncharacterized, spontaneous, autosomal recessive mouse mutation resulting in very tight, thick skin. wrfr mutant mice exhibit severe breathing difficulties secondary to their tight skin and die shortly after birth. This phenotype is strikingly similar to a very rare human genetic disorder, restrictive dermopathy. wrfr mutant mice display a defective skin barrier, which is normally imparted by the cornified envelope, a composite of protein and lipid that prevents loss of water from within and entry of potentially harmful substances from without. In addition, hair growth from grafted wrfr skin is impaired. Positional cloning of the wrfr mutation revealed a retrotransposon insertion into a coding exon of Slc27a4, the gene encoding fatty acid transport protein (FATP)4. FATP4 is the primary intestinal FATP and is thought to play a major role in dietary fatty acid uptake; it therefore is viewed as a target to prevent or reverse obesity. However, its function in vivo had not been determined. Our results demonstrate an unexpected yet critical role for FATP4 in skin and hair development and suggest Slc27a4 to be a candidate gene for restrictive dermopathy.

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