Insertion of long interspersed element‐1 in theMitfgene is associated with altered neurobehavior of the black‐eyed whiteMitf^mi‐bwmouse

Abstract

Microphthalmia-associated transcription factor (Mitf) is required for the differentiation of melanoblasts of the neural crest origin. The mouse homozygous for the black-eyed white (Mitf mi-bw ) allele is characterized by white-coat color and deafness with black eye, due to the loss of melanoblasts during embryonic development. The Mitf mi-bw allele carries an insertion of long interspersed element-1 (L1) in intron 3 of the Mitf gene, which may cause the deficiency of melanocyte-specific Mitf-M. Here, we show that the L1 insertion results in the generation of alternatively spliced Mitf-M mRNA species, such as Mitf-M mRNA lacking exon 3, exon 4 or both exons 3 and 4, each of which encodes Mitf-M protein with an internal deletion. Transient expression assays showed the loss of or reduction in function of each aberrant Mitf-M protein and the dominant negative effect of Mitf-M lacking exon 4 that encodes an activation domain. Thus, the L1 insertion may decrease the expression level of functional Mitf-M. Importantly, Mitf-M mRNA is expressed in the wild-type mouse brain, with the highest expression level in the hypothalamus. Likewise, aberrant Mitf-M mRNAs are expressed in the bw mouse brain. The bw mice show the altered neurobehavior under a stressful environment, suggesting the role of Mitf-M in sensory perception.

Microphthalmia‐associated transcription factor is expressed in projection neurons of the mouse olfactory bulb

“…In our preceding report (Takeda et al . ), we were unable to identify the cells that express Mitf in the brain using a commercially available antibody. We therefore decided to use our own polyclonal antibody against the His‐Tag‐MITF‐M that was produced in 1999 (Fuse et al .…”

“…) and marginally altered behavior (Takeda et al . ), suggesting the disturbance in a certain neural network. In fact, by the real‐time RT‐PCR analysis, we have shown the expression of Mitf‐M mRNA in the C57BL/6 mouse brain as well as in the homozygous Mitf mi‐bw mouse brain (Takeda et al .…”

“…In fact, by the real‐time RT‐PCR analysis, we have shown the expression of Mitf‐M mRNA in the C57BL/6 mouse brain as well as in the homozygous Mitf mi‐bw mouse brain (Takeda et al . , ). These results suggest that the expression of Mitf‐M may be regulated in the brain through the different mechanism from that in melanocytes.…”

Dysregulated Expression of MITF in Subsets of Hepatocellular Carcinoma and Cholangiocarcinoma

“…However, subsequent studies have suggested the pleiotropic functions of Mitf in various organs, including liver (Smith et al 1994), pancreas (Mazur et al 2013), kidney , lung (Takeda et al 2007), olfactory bulb (Ohba et al 2015), and frontal cortex (Takeda et al 2014;Ohba et al 2016). In particular, the Mitf vitiligo mouse, Mitf vit /Mitf vit , is characterized by retinal degeneration and the accumulation of retinyl palmitate in RPE and the liver (Smith et al 1994).…”

Microphthalmia-associated transcription factor as the molecular target of cadmium toxicity in human melanocytes

“…Thus, the amount of functional MITF is critical for maintaining the functions of melanocytes in humans. Likewise, Mitf-M, the mouse counterpart of human MITF-M, is essential for the development of follicular and choroidal melanocytes [3,8] and cochlear melanocytes [9,10]. The blood vessel-enriched choroid is located adjacent to the RPE that constitutes the blood-retinal barrier that protects the photoreceptors against blood-born toxicants [11].…”