Alternative titles; symbols
HGNC Approved Gene Symbol: ASCL1
Cytogenetic location: 12q23.2 Genomic coordinates (GRCh38): 12:102,957,674-102,960,513 (from NCBI)
Basic helix-loop-helix transcription factors of the achaete-scute family are instrumental in Drosophila neurosensory development and are candidate regulators of development in the mammalian central nervous system and neural crest. Ball et al. (1993) isolated and characterized a human achaete-scute homolog that is highly expressed in 2 neuroendocrine cancers, medullary thyroid cancer (MTC; 155240) and small cell lung cancer (SCLC; 182280). The human gene, ASCL1, which was symbolized ASH1 by the authors, was cloned from a human MTC cDNA library. It encodes a predicted protein of 238 amino acids that shares 95% identity with the mammalian achaete-scute homolog-1 (Mash1), a rodent basic helix-loop-helix factor. The proximal coding region of the cDNA contains a striking 14-copy repeat of the triplet CAG that exhibits polymorphism in human genomic DNA; thus, ASCL1 is a candidate locus. Northern blot analysis revealed ASCL1 transcripts in RNA from a human MTC cell line, 2 fresh MTC tumors, fetal brain, and 3 lines of human SCLC. In contrast, cultured lines of non-SCLC lung cancers and a panel of normal adult human tissues showed no detectable ASCL1 transcripts.
Ahmad (1995) found that Mash1 is expressed during development of rat retina and interacts specifically with an E-box identified in the promoter for the opsin gene during rod photoreceptor differentiation.
Using retroviral labeling in organotypic slice cultures of the embryonic human forebrain, Letinic et al. (2002) demonstrated the existence of 2 distinct lineages of neocortical GABAergic neurons. One lineage expresses DLX1 (600029) and DLX2 (126255) and MASH1 transcription factors, represents 65% of neocortical GABAergic neurons in humans, and originates from MASH1-expressing progenitors of the neocortical ventricular and subventricular zone of the dorsal forebrain. The second lineage, characterized by the expression of DLX1 and DLX2 but not MASH1, forms around 35% of the GABAergic neurons and originates from the ganglionic eminence of the ventral forebrain. Letinic et al. (2002) suggested that modifications in the expression pattern of transcription factors in the forebrain may underlie species-specific programs for the generation of neocortical local circuit neurons and that distinct lineages of cortical interneurons may be differentially affected in genetic and acquired diseases of the human brain.
Pattyn et al. (2004) noted that Ascl1 is coexpressed with Nkx2.2 (604612) in the neuroepithelial domain of the hindbrain, which gives rise to 5-HT neurons. In Ascl1 null mouse embryo brains, Pattyn et al. (2004) showed that 5-HT neurons were virtually absent from the earliest stages of differentiation. In the mouse, Ascl1 was essential for the birth of 5-HT neurons, both as a proneural gene for the production of postmitotic neuronal precursors and as a determinant of the serotonergic phenotype for the parallel activation of Gata3 (131320), Lmx1b (602575), and Pet1 (607150).
Miyoshi et al. (2004) presented evidence that Heslike (HELT; 617546) enhanced Ascl-dependent specification of GABAergic neurons in developing mouse brain.
Activation of Delta genes, such as Delta1 (DLL1; 606582), by proneural factors is an evolutionarily conserved step in neurogenesis that results in activation of Notch (see 190198) signaling and maintenance of an undifferentiated state in a subset of neural progenitors. Castro et al. (2006) showed that activation of mouse Delta1 involved cooperative binding of Mash1 and Brn1 (POU3F3; 602480)/Brn2 (POU3F2; 600494) to an evolutionarily conserved motif in the Delta1 gene. They identified the MASH1/BRN-binding motif in several other human, mouse, and rat genes, suggesting that MASH1 and BRN proteins synergistically regulate genes that control multiple aspects of the neurogenic program.
Vierbuchen et al. (2010) hypothesized that combinatorial expression of neural lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of 19 candidate genes, Vierbuchen et al. (2010) identified a combination of only 3 factors, Ascl1, Brn2 (600494), and Myt1l (613084), that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal cells express multiple neuron-specific proteins, generate action potentials, and form functional synapses.
Pang et al. (2011) showed that POU3F2 (600494), ASCL1, and MYT1L can generate functional neurons from human pluripotent stem cells as early as 6 days after transgene activation. When combined with NEUROD1 (601724), these factors could also convert fetal and postnatal human fibroblasts into induced neuronal cells showing typical neuronal morphologies and expressing multiple neuronal markers, even after downregulation of the exogenous transcription factors. Importantly, the vast majority of human induced neuronal cells were able to generate action potentials and many matured to receive synaptic contacts when cocultured with primary mouse cortical neurons. Pang et al. (2011) concluded that nonneuronal human somatic cells, as well as pluripotent stem cells, can be converted directly into neurons by lineage-determining transcription factors.
Caiazzo et al. (2011) identified a minimal set of 3 transcription factors--Mash1, Nr4a2 (601828), and Lmx1a (600298)--that are able to generate directly functional dopaminergic neurons from mouse and human fibroblasts without reverting to a progenitor cell stage. Induced dopaminergic cells released dopamine and showed spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain dopaminergic neurons. The 3 factors were able to elicit dopaminergic neuronal conversion in prenatal and adult fibroblasts from healthy donors and Parkinson disease (168600) patients.
Yoo et al. (2011) demonstrated that expression of miR9/9* (see 611186) and miR124 (609327) in human fibroblasts induced their conversion into neurons, a process facilitated by NEUROD2 (601725). Further addition of neurogenic transcription factors ASCL1 and MYT1L enhanced the rate of conversion and the maturation of the converted neurons, whereas expression of these transcription factors without the aforementioned microRNAs was ineffective. Yoo et al. (2011) concluded that the genetic circuitry involving miR9-1 through miR9-3 and miR124 can have an instructive role in neural fate determination.
The basic helix-loop-helix transcription factors ASCL1, HES1 (139605), and OLIG2 (606386) regulate fate choice of neurons, astrocytes, and oligodendrocytes, respectively. These same factors are coexpressed by neural progenitor cells. Imayoshi et al. (2013) found by time-lapse imaging that these factors are expressed in an oscillatory manner by mouse neural progenitor cells. In each differentiation lineage, 1 of the factors becomes dominant. Imayoshi et al. (2013) used optogenetics to control expression of Ascl1 and found that, although sustained Ascl1 expression promotes neuronal fate determination, oscillatory Ascl1 expression maintains proliferating neural progenitor cells. Imayoshi et al. (2013) concluded that the multipotent state correlates with oscillatory expression of several fate-determination factors, whereas the differentiated state correlates with sustained expression of a single factor.
Dyachuk et al. (2014) showed that the parasympathetic system in mice, including trunk ganglia and the cranial ciliary, pterygopalatine, lingual, submandibular, and otic ganglia, arises from glial cells in nerves, not neural crest cells. Dyachuk et al. (2014) further showed that neurons are recruited from glial progenitors dwelling in cranial and trunk nerves by a local induction of the Ascl1 gene. The parasympathetic fate is induced in nerve-associated Schwann cell precursors at distal peripheral sites. Using multicolor Cre-reporter lineage tracing, Dyachuk et al. (2014) showed that most of these neurons arise from bipotent progenitors that generate both glia and neurons. This nerve origin places cellular elements for generating parasympathetic neurons in diverse tissues and organs.
Urban et al. (2016) demonstrated that HUWE1 (300697) is required for proliferating stem cells of the adult mouse hippocampus to return to quiescence. HUWE1 destabilizes proactivation protein ASCL1 in proliferating hippocampal stem cells, which prevents accumulation of cyclin Ds and promotes the return to a resting state. When stem cells fail to return to quiescence, the proliferative stem cell pool becomes depleted.
Jorstad et al. (2017) showed that Muller glia (MG)-specific overexpression of Ascl1, together with a histone deacetylase (HDAC) inhibitor, enables adult mice to generate neurons from MG after retinal injury. The MG-derived neurons express markers of inner retinal neurons, synapse with host retinal neurons, and respond to light. Using an assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), Jorstad et al. (2017) showed that the HDAC inhibitor promotes accessibility at key gene loci in the MG, and allows more effective reprogramming.
By analysis of rodent/human somatic cell hybrids, Ball et al. (1993) assigned the ASCL1 gene to human chromosome 12. Renault et al. (1995) mapped ASCL1 onto a YAC contig distal to PAH (612349) and proximal to TRA1 (191175). The authors used fluorescence in situ hybridization to determine the cytogenetic assignment of 12q22-q23.
Reclassified Variants
Three variants in the ASCL1 gene reported by de Pontual et al. (2003)--P18T (100790.0001), a 15-bp del (100790.0002), and a 24-bp deletion (100790.0003)--in patients with congenital central hypoventilation syndrome (CCHS; see 209800) have been reclassified as variants of unknown significance.
By homologous recombination in embryonic stem cells, Guillemot et al. (1993) created a null allele of the Mash1 gene. Homozygous mice died at birth with apparent breathing and feeding defects. The brain and spinal cord appeared normal, but the olfactory epithelium and sympathetic, parasympathetic, and enteric ganglia were severely affected. These observations suggested that the Mash1 gene, like its Drosophila homologs, controls a basic operation in development of neuronal progenitors in distinct neural lineages.
Kokubu et al. (2008) found that Mash1 was highly expressed in mouse glandular stomach epithelium. At embryonic day 18.5, almost all gastric neuroendocrine cells were missing in Mash1-null mice, whereas development of nonneuroendocrine cells appeared normal. Ngn3 (NEUROG3; 604882), which regulates formation of gastrin (GAS; 137250)-, glucagon (GCG; 138030)-, and somatostatin (SST; 182450)-producing gastric neuroendocrine cells, was expressed normally in Mash1-null stomach. Kokubu et al. (2008) concluded that a subset of gastric neuroendocrine cells requires both NGN3 and MASH1 for their development, while other neuroendocrine cells require MASH1 alone.
This variant, formerly designated CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, has been reclassified as a variant of unknown significance because the patient reported by de Pontual et al. (2003) also had a mutation in the PHOX2B gene, a known cause of CCHS.
In a patient with CCHS (see 209880), de Pontual et al. (2003) identified heterozygosity for a 52C-A transversion in the ASCL1 gene, resulting in a pro18-to-thr substitution. The patient was also heterozygous for a polyalanine expansion mutation in PHOX2B (603851).
This variant, formerly designated CENTRAL HYPOVENTILATION SYNDROME, CONGENITAL, has been reclassified as a variant of unknown signficance based on a personal communication by Hamosh (2021) noting that the effect of this polyalanine tract contraction was similar to that of the missense mutation in ASCL1 (100790.0001) as reported by de Pontual et al. (2003) and that contraction of polyalanine tracts is not a typical pathogenetic mechanism. No additional mutations in ASCL1 have been reported as a cause of CCHS.
In a patient with congenital hypoventilation syndrome (CCHS; see 209880), de Pontual et al. (2003) identified heterozygosity for a 15-bp deletion (111-115del15nt) in the ASCL1 gene. The mutation was predicted to result in loss of 5 of 13 alanine residues (ala37-ala41) in a polyalanine tract.
This variant, formerly designated HADDAD SYNDROME, has been reclassified as a variant of unknown signficance based on a personal communication from Hamosh (2021) noting that the effect of this polyalanine tract contraction was similar to that of the missense mutation in ASCL1 (100790.0001) as reported by de Pontual et al. (2003) and that contraction of polyalanine tracts is not a typical pathogenetic mechanism. No additional mutations in ASCL1 have been reported as a cause of Haddad syndrome.
In a patient with Haddad syndrome (see 209880), de Pontual et al. (2003) identified heterozygosity for a 24-bp deletion (108-131del24nt) in the ASCL1 gene. The mutation was predicted to result in loss of 8 of 13 alanine residues (ala36-ala43) in a polyalanine tract.
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