The underestimated role of the microphthalmia-associated transcription factor (MiTF) in normal and pathological haematopoiesis

Abstract

Haematopoiesis, the process by which a restrained population of stem cells terminally differentiates into specific types of blood cells, depends on the tightly regulated temporospatial activity of several transcription factors (TFs). The deregulation of their activity or expression is a main cause of pathological haematopoiesis, leading to bone marrow failure (BMF), anaemia and leukaemia. TFs can be induced and/or activated by different stimuli, to which they respond by regulating the expression of genes and gene networks. Most TFs are highly pleiotropic; i.e., they are capable of influencing two or more apparently unrelated phenotypic traits, and the action of a single TF in a specific setting often depends on its interaction with other TFs and signalling pathway components. The microphthalmia-associated TF (MiTF) is a prototype TF in multiple situations. MiTF has been described extensively as a key regulator of melanocyte and melanoma development because it acts mainly as an oncogene. Mitf-mutated mice show a plethora of pleiotropic phenotypes, such as microphthalmia, deafness, abnormal pigmentation, retinal degeneration, reduced mast cell numbers and osteopetrosis, revealing a greater requirement for MiTF activity in cells and tissue. A growing amount of evidence has led to the delineation of key roles for MiTF in haematopoiesis and/or in cells of haematopoietic origin, including haematopoietic stem cells, mast cells, NK cells, basophiles, B cells and osteoclasts. This review summarizes several roles of MiTF in cells of the haematopoietic system and how MiTFs can impact BM development.

The Role and Regulatory Mechanism of Transcription Factor EB in Health and Diseases

“…Within family members, the domains outside BHLH-LZ are quite different. TFEB has a glutamine-rich domain (Gln) and a proline-rich domain (Pro) ( Oppezzo and Rosselli, 2021 ). MITF and TFEC has a serine-rich domain (Ser), while TFE3 has a proline- and arginine-rich domain (Pro + Arg) ( Oppezzo and Rosselli, 2021 ).…”

“…TFEB has a glutamine-rich domain (Gln) and a proline-rich domain (Pro) ( Oppezzo and Rosselli, 2021 ). MITF and TFEC has a serine-rich domain (Ser), while TFE3 has a proline- and arginine-rich domain (Pro + Arg) ( Oppezzo and Rosselli, 2021 ). In invertebrates, orthologs of MITF/TFE family also exist, including helix-loop-helix transcription factor 30 (HLH-30) in Caenorhabditis elegans ( Rehli et al, 1999a ) and MITF in Drosophila melanogaster ( Hallsson et al, 2004 ).…”

Anaphylaxis: Focus on Transcription Factor Activity

“…The microphthalmia-associated transcription factor (MITF) is involved in the generation and function of mast cells [ 103 ], melanocytes [ 104 ], osteoclast [ 105 , 106 ], and retinal pigmented epithelium [ 107 ]. There are several isoforms described, MITF-A, -B, -C, -D, -E, -H, -M, Mc, and -J, differing in their exon 1 and sharing common downstream exons from 2 to 9 [ 108 ].…”

MiT Family Transcriptional Factors in Immune Cell Functions

“…The microphthalmia-associated transcription factor family (MiT family) consists of four transcription factors: MITF (microphthalmia-associated transcription factor or melanocyte-inducing transcription factor), TFEB (transcription factor EB), TFE3 (transcription factor E3), and TFEC (transcription factor EC) ( Goding and Arnheiter, 2019 ; Napolitano and Ballabio, 2016 ; Oppezzo and Rosselli, 2021 ). The Mitf gene encoding the first member of the MiT family, MITF, was discovered in 1993 and mutations of Mitf were demonstrated to account for the phenotypes of ‘ microphthalmia ( mi )’ mice which were originally described in 1942 to have small (microphthalmic) eyes ( Hertwig, 1942 ; Hodgkinson et al, 1993 ; Krakowsky et al, 1993 ).…”

“…TFEB and TFE3 are ubiquitously expressed whereas MITF and TFEC show more tissue-specific expression patterns. Additionally, the Mitf gene has several transcription start sites and its primary RNAs are subjected to various modes of alternative splicing, resulting in at least 12 different protein isoforms ( Oppezzo and Rosselli, 2021 ). Expression of individual MITF isoforms seems to be tissue-specific.…”