|
?The Role of HOX Proteins in Mammary Development
|
|
By CourteneyLai, Section Biology
Posted on Fri Apr 30th, 2010 at 02:11:42 PM PST
|
 |
|
The homeobox (Hox) genes are a group of regulatory genes that encode a conserved family of transcription factors known to play key roles in specifying cell fate and identity during development.[1] Accumulating evidence suggests that they are also master regulators of organogenesis in adult tissues and mediators of lineage determination in early hematopoiesis.[2, 3] Recent gene expression analyses as well as gain and loss-of-function studies have demonstrated that several Hox genes are critically important for normal mammary gland development and function.[4] In addition to their role in normal development and differentiation, the perturbation of Hox genes in neoplastic breast tissue in comparison to non-malignant breast tissue indicates an underlying function in the regulation of cell differentiation and specification of mammary epithelial cells. Altered Hox gene expression has been detected in human breast tumors but has also been implicated in diseases of the hematopoietic system.[5, 6]
|
Early studies of Hox genes in the mammary gland have been restricted to the detection of many of these genes using in situ hybridizations and northern blots; although the use of knockout mice to study the effects on mammary gland development has also become more common.[4] The manner in which Hox gene expression levels are studied in the entire mammary gland may in fact be masking changes that are occurring in specific cellular subtypes within the gland. It is possible that certain subpopulations play pivotal roles in mediating temporal Hox gene expression patterns that are observed throughout development (reviewed below). Since recent landmark studies have developed sensitive, quantitative and specific assays for detecting and characterizing normal mammary stem and progenitor cell populations in mice, they have paved the way for beginning to analyze the specific expression patterns of candidate Hox genes that confer particular differentiation states in stem/progenitor cell populations.
I hypothesized that some Hox genes might be differentially expressed in distinct functional and phenotypic subpopulations of the mammary gland and that this will provide us with novel information about their roles in regulating mammary lineage specification. It is possible that Hox genes are candidate genes that may regulate the self-renewal and/or differentiation of mammary stem and progenitor cells. My hypothesis is supported by studies in the hematopoietic system where Hox genes have been extensively investigated and have been identified as regulators of early hematopoiesis.[6] Notably, certain Hox genes are preferentially expressed in hematopoietic stem cell-enriched and immature progenitor compartments in stage and lineage-specific patterns.[7]
I suggest performing fluorescence-activated cell sorting (FACS) isolation to isolate mammary cell subpopulations stem cells (CD49fhiCD24int), luminal progenitor cells (CD49floCD24hi), and mature myoepithelial cells (CD49fintCD24lo) from mammary glands.[8] Using microfluidic technology, we could then track Hox protein expression patterns (burst size and frequency) in real-time in each of the three developmental stages described.[9] This technology is of particular use in the stem and progenitor cell populations, which exist at low numbers within the normal mammary gland. By mapping the stochastic HOX protein expression, we can determine the length of time and interplay of these proteins, which may lead to indications of their role(s) in mammary development.
REFERENCES
1. Mark, M., F.M. Rijli, and P. Chambon, Homeobox genes in embryogenesis and pathogenesis. Pediatr Res, 1997. 42(4): p. 421-9.
2. Ford, H.L., Homeobox genes: a link between development, cell cycle, and cancer? Cell Biol Int, 1998. 22(6): p. 397-400.
3. Lawrence, H.J., et al., The role of HOX homeobox genes in normal and leukemic hematopoiesis. Stem Cells, 1996. 14(3): p. 281-91.
4. Friedmann, Y., et al., Hox genes in normal and neoplastic mouse mammary gland. Cancer Res, 1994. 54(22): p. 5981-5.
5. Abate-Shen, C., Deregulated homeobox gene expression in cancer: cause or consequence? Nat Rev Cancer, 2002. 2(10): p. 777-85.
6. van Oostveen, J., et al., The role of homeobox genes in normal hematopoiesis and hematological malignancies. Leukemia, 1999. 13(11): p. 1675-90.
7. Sauvageau, G., et al., Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev, 1995. 9(14): p. 1753-65.
8. Stingl, J., et al., Purification and unique properties of mammary epithelial stem cells. Nature, 2006. 439(7079): p. 993-7.
9. Cai, L., N. Friedman, and X.S. Xie, Stochastic protein expression in individual cells at the single molecule level. Nature, 2006. 440(7082): p. 358-62. |
|
|
|
|
|
|
