Achaete-scute homolog 1 is a protein that in humans is encoded by the ASCL1gene.[1][2] Because it was discovered subsequent to studies on its homolog in Drosophila, the Achaete-scute complex, it was originally named MASH-1 for mammalian achaete scute homolog-1.[3]
This gene encodes a member of the basic helix-loop-helix (BHLH) family of transcription factors. The protein activates transcription by binding to the E box (5'-CANNTG-3'). Dimerization with other BHLH proteins is required for efficient DNA binding. This protein plays a role in the neuronal commitment and differentiation and in the generation of olfactory and autonomic neurons. It is highly expressed in medullary thyroid cancer and small cell lung cancer and may be a useful marker for these cancers. The presence of a CAG repeat in the gene suggests that it may also play a role in tumor formation.[2]
Role in neuronal commitment
Development of the vertebrate nervous system begins when the neural tube forms in the early embryo. The neural tube eventually gives rise to the entire nervous system, but first neuroblasts must differentiate from the neuroepithelium of the tube. The neuroblasts are the cells that undergo mitotic division and produce neurons.[3] Asc is central to the differentiation of the neuroblasts and the lateral inhibition mechanism which inherently creates a safety net in the event of damage or death in these incredibly important cells.[3]
Differentiation of the neuroblast begins when the cells of the neural tube express Asc and thus upregulate the expression of Delta, a protein essential to the lateral inhibition pathway of neuronal commitment.[3] Delta can diffuse to neighboring cells and bind to the Notch receptor, a large transmembrane protein which upon activation undergoes proteolytic cleavage to release the intracellular domain (Notch-ICD).[3] The Notch-ICD is then free to travel to the nucleus and form a complex with Suppressor of Hairless (SuH) and Mastermind.[3] This complex acts as transcription regulator of Asc and accomplishes two important tasks. First, it prevents the expression of factors required for differentiation of the cell into a neuroblast.[3] Secondly, it inhibits the neighboring cell's production of Delta.[3] Therefore, the future neuroblast will be the cell that has the greatest Asc activation in the vicinity and consequently the greatest Delta production that will inhibit the differentiation of neighboring cells. The select group of neuroblasts that then differentiate in the neural tube are thus replaceable because the neuroblast's ability to suppress differentiation of neighboring cells depends on its own ability to produce Asc.[3]
This process of neuroblast differentiation via Asc is common to all animals.[3] Although this mechanism was initially studied in Drosophila, homologs to all proteins in the pathway have been found in vertebrates that have the same bHLH structure.[3]
Autonomic nervous system development
In addition to its important role in neuroblast formation, Asc also functions to mediate autonomic nervous system (ANS) formation.[4] Asc was initially suspected to play a role in the ANS when ASCL1 was found expressed in cells surrounding the dorsal aorta, the adrenal glands and in the developing sympathetic chain during a specific stage of development.[4] Subsequent studies of mice genetically altered to be MASH-1 deficient revealed defective development of both sympathetic and parasympathetic ganglia, the two constituents of the ANS.[4]
↑ 4.04.14.2Axelson H (Feb 2004). "The Notch signaling cascade in neuroblastoma: role of the basic helix-loop-helix proteins HASH-1 and HES-1". Cancer Letters. 204 (2): 171–8. doi:10.1016/s0304-3835(03)00453-1. PMID15013216.
↑Mao Z, Nadal-Ginard B (Jun 1996). "Functional and physical interactions between mammalian achaete-scute homolog 1 and myocyte enhancer factor 2A". The Journal of Biological Chemistry. 271 (24): 14371–5. doi:10.1074/jbc.271.24.14371. PMID8662987.
Further reading
Chen H, Kunnimalaiyaan M, Van Gompel JJ (Jun 2005). "Medullary thyroid cancer: the functions of raf-1 and human achaete-scute homologue-1". Thyroid. 15 (6): 511–21. doi:10.1089/thy.2005.15.511. PMID16029117.
Renault B, Lieman J, Ward D, Krauter K, Kucherlapati R (Nov 1995). "Localization of the human achaete-scute homolog gene (ASCL1) distal to phenylalanine hydroxylase (PAH) and proximal to tumor rejection antigen (TRA1) on chromosome 12q22-q23". Genomics. 30 (1): 81–3. doi:10.1006/geno.1995.0012. PMID8595908.
Mao Z, Nadal-Ginard B (Jun 1996). "Functional and physical interactions between mammalian achaete-scute homolog 1 and myocyte enhancer factor 2A". The Journal of Biological Chemistry. 271 (24): 14371–5. doi:10.1074/jbc.271.24.14371. PMID8662987.
Borges M, Linnoila RI, van de Velde HJ, Chen H, Nelkin BD, Mabry M, Baylin SB, Ball DW (Apr 1997). "An achaete-scute homologue essential for neuroendocrine differentiation in the lung". Nature. 386 (6627): 852–5. doi:10.1038/386852a0. PMID9126746.
Chen H, Biel MA, Borges MW, Thiagalingam A, Nelkin BD, Baylin SB, Ball DW (Jun 1997). "Tissue-specific expression of human achaete-scute homologue-1 in neuroendocrine tumors: transcriptional regulation by dual inhibitory regions". Cell Growth & Differentiation. 8 (6): 677–86. PMID9186001.
Lo L, Sommer L, Anderson DJ (Jun 1997). "MASH1 maintains competence for BMP2-induced neuronal differentiation in post-migratory neural crest cells". Current Biology. 7 (6): 440–50. doi:10.1016/S0960-9822(06)00191-6. PMID9197246.
Rozovskaia T, Rozenblatt-Rosen O, Sedkov Y, Burakov D, Yano T, Nakamura T, Petruck S, Ben-Simchon L, Croce CM, Mazo A, Canaani E (Jan 2000). "Self-association of the SET domains of human ALL-1 and of Drosophila TRITHORAX and ASH1 proteins". Oncogene. 19 (3): 351–7. doi:10.1038/sj.onc.1203307. PMID10656681.
Persson P, Jögi A, Grynfeld A, Påhlman S, Axelson H (Jul 2000). "HASH-1 and E2-2 are expressed in human neuroblastoma cells and form a functional complex". Biochemical and Biophysical Research Communications. 274 (1): 22–31. doi:10.1006/bbrc.2000.3090. PMID10903890.
Westerman BA, Neijenhuis S, Poutsma A, Steenbergen RD, Breuer RH, Egging M, van Wijk IJ, Oudejans CB (Apr 2002). "Quantitative reverse transcription-polymerase chain reaction measurement of HASH1 (ASCL1), a marker for small cell lung carcinomas with neuroendocrine features". Clinical Cancer Research. 8 (4): 1082–6. PMID11948117.
Letinic K, Zoncu R, Rakic P (Jun 2002). "Origin of GABAergic neurons in the human neocortex". Nature. 417 (6889): 645–9. doi:10.1038/nature00779. PMID12050665.
de Pontual L, Népote V, Attié-Bitach T, Al Halabiah H, Trang H, Elghouzzi V, Levacher B, Benihoud K, Augé J, Faure C, Laudier B, Vekemans M, Munnich A, Perricaudet M, Guillemot F, Gaultier C, Lyonnet S, Simonneau M, Amiel J (Dec 2003). "Noradrenergic neuronal development is impaired by mutation of the proneural HASH-1 gene in congenital central hypoventilation syndrome (Ondine's curse)". Human Molecular Genetics. 12 (23): 3173–80. doi:10.1093/hmg/ddg339. PMID14532329.
Sippel RS, Carpenter JE, Kunnimalaiyaan M, Chen H (Dec 2003). "The role of human achaete-scute homolog-1 in medullary thyroid cancer cells". Surgery. 134 (6): 866–71, discussion 871–3. doi:10.1016/s0039-6060(03)00418-5. PMID14668716.
Ferretti E, Di Stefano D, Zazzeroni F, Gallo R, Fratticci A, Carfagnini R, Angiulli S, Santoro A, Minniti G, Tamburrano G, Alesse E, Cantore G, Gulino A, Jaffrain-Rea ML (Oct 2003). "Human pituitary tumours express the bHLH transcription factors NeuroD1 and ASH1". Journal of Endocrinological Investigation. 26 (10): 957–65. doi:10.1007/bf03348192. PMID14759067.