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ascl1

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Official Full Name
achaete-scute family bHLH transcription factor 1
Background
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. Mutations in this gene may contribute to the congenital central hypoventilation syndrome (CCHS) phenotype in rare cases. [provided by RefSeq, Jul 2008]
Synonyms
ASCL1; achaete-scute family bHLH transcription factor 1; ASH1; HASH1; MASH1; bHLHa46; achaete-scute homolog 1; ASH-1; achaete scute protein; achaete-scute complex-like 1; achaete-scute complex homolog 1; class A basic helix-loop-helix protein 46; achaete-scute complex homolog 1 (Drosophila)

ASCL1 is an important member of the basic-helix-loop helix (bHLH) transcriptional regulator family. First discovered in the fruit fly. The study found that it can promote the differentiation of highly differentiated and strong energy cells into neurons, which are indispensable in the development of peripheral nervous system and central nervous system. Therefore, ASCL1 is considered to be an important neural precursor factor.

ASCL1 and Differentiation

Nakatani studies have shown that oligodendrocytes are myelin cells of the central nervous system. Examination of myelin regeneration in a mouse model Demyelination and human multiple sclerosis showed that ASCL1 activity was up-regulated with increased oligodendrocytes during remyelination. ASCL1 is expressed in cortical SVZ progenitor cells and the oligodendrocyte precursor cells (OPCs) they produce, and is down-regulated during oligodendrocyte differentiation. ASCL1 is maintained at a low level in adult OPCs, and its level is up-regulated to ASC1 function during demyelination, which is required for normal OPC differentiation during remyelination.

Figure 1. Working model for Ascl1 function in oligodendrogenesis. (Nakatani, H., et al, 2013)

Müller glial cells are a source of retinal regeneration in fish and birds. ASCL1 is required for retinal regeneration of fish but not after retinal damage in mice. Further studies revealed that transgenic expression of ASCL1 in adult Müller glial cells in uninjured retina did not significantly affect its phenotype. However, when the retina is damaged, glial cells expressing ASCL1 elicit a response similar to the early stages of zebrafish retinal regeneration. The findings provide a further study for stimulating retinal regeneration in the treatment of eye diseases.

The transdifferentiation process of astrocytes induced by ASCL1 single factor can be achieved in the juvenile brain and adult brain, respectively (two weeks after birth). It is sufficient to convert astrocytes in multiple brain regions of juvenile and adult mice into neurons simply by transferring a transcription factor called ASCL1. Liu et al. used adenovirus (AAV) transfection to express a single transcription factor, ASCL1, specifically in astrocytes in the midbrain, striatum and cortex of the brain. As a result, it was found that astrocytes can be efficiently transdifferentiated into neurons directly in vivo. This research has established a new and efficient method for obtaining functional neurons in body transdifferentiation, providing an important way to achieve nerve repair in the brain or traumatic brain.

Vierbuchen et al. tested various combinations and found that only five transcription factors, ASCL1, Brn2/4, Myt1l, Zic1 and Olig2, were required to convert fibroblasts into neuronal cells capable of expressing GFP protein. They refer to this neuronal cell as an induced neuronal (iN) cell, and only ACl1 is required.

ASCL1 and SCLC

ASCL1 is a member of the bHLH gene family. As a transcription factor, ASCL1 not only plays an important role in the neuroendocrine differentiation of tumors but also increases the metastasis and invasion ability of neuroendocrine tumors by inducing EMT. Small cell lung cancer (SCLC) is a common NET, and the differentiation of human and neuroendocrine tissues depends on the role of ASCL1.

Studies have found that the alpha subunit of the epithelial sodium channel (αENaC) encoded by SCNN1A is associated with ASCL1 expression levels in SCLC, and αENaC is highly expressed in ASCL1-dependent (ASCL1 high expression) SCLC. Knocking out the ASCL1 gene during mouse embryonic development results in the loss of neuroendocrine cells in the lung. Instead, in the turn overexpression of ASCL1 in gene mice promotes airway epithelial hyperplasia, and co-transfection of ASCL1 with SV40 (simian virus 40) large T antigen can promote lung tumor formation with neuroendocrine characteristics.

To determine whether αENaC inhibition can mimic the loss of function of ASCL1 to reduce cell viability, the study tested the effect of amiloride on H889 ASCL1 high expression and H82ASCL1 low expression SCLC cells and Yonghua HBEC3KT cell viability. As the concentration of amiloride increased, the activity of H889 cells decreased, but had no effect on the activity of H82 or HBEC3KT cells. These studies indicate that SCNN1A/αENaC is a direct transcriptional target of the SCLC germline-specific gene ASCL1, which can be used for pharmacological targeting for anti-tumor effects.

ASCL1 and Other Diseases

Transfection studies of the ASCL1 gene in human adenocarcinoma cell lines have been reported, and neuroendocrine differentiation functions have been confirmed in transfected cells. ASCL1-transfected lung cancer cells display an amoeba migration phenotype that may be associated with deletion of the E-cadherin /β - Catenin complex. When transfected with the ASCL1 gene, adenocarcinoma cells lose their adhesion and float in the culture dish. In the ASCL1 transfected cells, in addition to the expression of neuroendocrine markers, EMT-related transcription factors such as Snail, Slug, and ZEB2 increased, while E-cadherin decreased. When ASCL1-transfected adenocarcinoma cells were transplanted into the subcutaneous tissue of immunodeficient mice, xenografted tumors consisted of small cells and large cells without epithelial structures, exhibiting undifferentiated histological features.

Studies have shown that ASCL1 is a neuroendocrine (NE) biomarker associated with lung adenocarcinoma (AD). Although other NE markers such as CHGA and SYP are commonly expressed in AD, only the binding of ASCL1 expression to RET shows a significant difference in clinical outcome, indicating a biological and clinically relevant pathway for NE differentiation.

References:

  1. Nakatani, H., Martin, E., Hassani, H., Clavairoly, A., Maire, C. L., & Viadieu, A., et al. (2013). Ascl1/mash1 promotes brain oligodendrogenesis during myelination and remyelination. Journal of Neuroscience, 33(23), 9752-9768.
  2. He M, Liu S, Callolu SK, et al. (2018)  The Epithelial Sodium Channel (alphaENaC) Is a Downstream Therapeutic Target of ASCL1 in Pulmonary Neuroendocrine Tumors. Transl Oncol, 11(2):292-299.
  3. Ueki, Y., Wilken, M. S., Cox, K. E., Chipman, L., Jorstad, N., & Sternhagen, K., et al. (2015). Transgenic expression of the proneural transcription factor ascl1 in muller glia stimulates retinal regeneration in young mice. Proceedings of the National Academy of Sciences of the United States of America, 112(44), 13717-22.
  4. Kosari, F., Ida, C. M., Aubry, M. C., Yang, L., Kovtun, I. V., & Klein, J. L. S., et al. (2014). Ascl1 and ret expression defines a clinically relevant subgroup of lung adenocarcinoma characterized by neuroendocrine differentiation. Oncogene, 33(29), 3776.
  5. Liu, Y., Miao, Q., Yuan, J., Han, S., Zhang, P., & Li, S., et al. (2015). Ascl1 converts dorsal midbrain astrocytes into functional neurons in vivo. Journal of Neuroscience, 35(25), 9336-9355.