Alternative titles; symbols
HGNC Approved Gene Symbol: ASCL2
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38): 11:2,268,498-2,270,588 (from NCBI)
The mammalian Achaete-Scute homologs are conserved mammalian cognates of the Drosophila Achaete-Scute complex. In rodents, 2 such genes have been identified: Mash1 (ASCL1; 100790), which is expressed in neuronal progenita, and Mash2 (ASCL2), which is expressed in spongiotrophoblast cells and their precursors. Both are members of the basic helix-loop-helix (bHLH) gene family, which includes MYC (190080) and MYOD1 (159970). Mash1 and Mash2 function as lineage-specific transcription factors essential for development of the neurectoderm and trophectoderm, respectively. Alders et al. (1997) noted that in mouse, the Mash2 gene is subject to genomic imprinting, with only the maternal allele being active. Alders et al. (1997) isolated the human homolog of the MASH2 gene, which they designated HASH2. Expression studies showed that HASH2 was expressed in extravillous trophoblast cells only. The lack of expression in nonmalignant hydatidiform (androgenetic) moles indicated that HASH2 is imprinted in man.
Luscher-Firzlaff et al. (2008) observed that human ASH2 cooperated with HRAS (190020) to transform primary rat embryo fibroblasts (REFs). Furthermore, transformation of REFs by MYC and HRAS required the presence of rat Ash2. In an animal model, human ASH2/HRAS-transformed REFs formed rapidly growing tumors characteristic of fibrosarcomas that, compared with tumors derived from MYC/HRAS-transformed cells, were poorly differentiated. ASH2 protein expression was increased in most human tumors and tumor cell lines examined, and knockdown of ASH2 inhibited proliferation in 2 human tumor cell lines. Luscher-Firzlaff et al. (2008) concluded that ASH2 can act as an oncoprotein.
Liu et al. (2014) showed that expression of ASCL2 is selectively upregulated in follicular T-helper (T-FH) cells. Ectopic expression of ASCL2 upregulated CXCR5 (601613) but not BCL6 (109565), and downregulated CCR7 (600242) expression in T cells in vitro, as well as accelerating T-cell migration to the follicles and T-FH cell development in vivo in mice. Genomewide analysis indicated that ASCL2 directly regulates T-FH-related genes, whereas it inhibits expression of T-helper-1 (TH1; see 606652) and TH17 (see 603149) signature genes. Acute deletion of ASCL2, as well as blockade of its function with the ID3 protein (600277) in CD4-positive T cells (see 186940), resulted in impaired T-FH-cell development. Conversely, mutation of ID3, known to cause antibody-mediated autoimmunity, greatly enhanced T-FH-cell generation and germinal center response. Liu et al. (2014) concluded that ASCL2 directly initiates T-FH-cell development.
Alders et al. (1997) noted that the mouse Mash2 gene maps to distal chromosome 7 and is closely linked to 3 other imprinted genes, Ins2 (176730), Igf2 (147470), and H19 (103280). They mapped the human HASH2 gene to the conserved syntenic human chromosome region 11p15.5. Alders et al. (1997) showed that the human gene maps proximal to and in close proximity of IGF2, and that the gene order in this region is HASH2-INS-IGF2-H19-tel.
Alders et al. (1997) noted that mice deficient for Mash2 die at 10 days postcoitum due to placental failure (Guillemot et al., 1994). In contrast, chimeric mice with heterozygous extraembryonic tissues and homozygous embryonic tissues are viable and normal, indicating that this gene, although essential for development of the placenta, is not important for development of the embryo proper. Mice carrying the homozygously mutated Mash2 gene die at 10 days postcoitum, as do heterozygous mice who inherited the mutant allele from their mother, consistent with genomic imprinting in which only the maternal allele is active. Heterozygous mice who inherited the mutant allele from their father are viable. This phenomenon of paternal imprinting of a gene being critical for development of a placenta is an exception to the common imprinting rule: nuclear transplantation studies in mice have shown that imprinting is biased toward embryonic versus extraembryonic tissues with preferential expression of the maternal and paternal alleles in the embryo and placenta, respectively.
Alders, M., Hodges, M., Hadjantonakis, A.-K., Postmus, J., van Wijk, I., Bliek, J., de Meulemeester, M., Westerveld, A., Guillemot, F., Oudejans, C., Little, P., Mannens, M. The human Achaete-Scute homologue 2 (ASCL2,HASH2) maps to chromosome 11p15.5, close to IGF2 and is expressed in extravillus (sic) trophoblasts. Hum. Molec. Genet. 6: 859-867, 1997. [PubMed: 9175731] [Full Text: https://doi.org/10.1093/hmg/6.6.859]
Guillemot, F., Nagy, A., Auerbach, A., Rossant, J., Joyner, A. L. Essential role of Mash-2 in extraembryonic development. Nature 371: 333-336, 1994. [PubMed: 8090202] [Full Text: https://doi.org/10.1038/371333a0]
Liu, X., Chen, X., Zhong, B., Wang, A., Wang, X., Chu, F., Nurieva, R. I., Yan, X., Chen, P., van der Flier, L. G., Nakatsukasa, H., Neelapu, S. S., Chen, W., Clevers, H., Tian, Q., Qi, H., Wei, L., Dong, C. Transcription factor achaete-scute homologue 2 initiates follicular T-helper-cell development. Nature 507: 513-518, 2014. [PubMed: 24463518] [Full Text: https://doi.org/10.1038/nature12910]
Luscher-Firzlaff, J., Gawlista, I., Vervoorts, J., Kapelle, K., Braunschweig, T., Walsemann, G., Rodgarkia-Schamberger, C., Schuchlautz, H., Dreschers, S., Kremmer, E., Lilischkis, R., Cerni, C., Wellmann, A., Luscher, B. The human trithorax protein hASH2 functions as an oncoprotein. Cancer Res. 68: 749-758, 2008. [PubMed: 18245475] [Full Text: https://doi.org/10.1158/0008-5472.CAN-07-3158]