Abstract Neuroplasticity forms the basis for neuronal circuit complexity and differences between otherwise similar circuits. We show that the Microphthalmia-associated transcription factor (Mitf) plays a central role in intrinsic plasticity of olfactory bulb (OB) projection neurons. Mitral and tufted (M/T) neurons from Mitf mutant mice are hyperexcitable, have a reduced Type-A potassium current (IA) and exhibit reduced expression of Kcnd3, which encodes a potassium voltage-gated channel subunit (Kv4.3) important for generating the IA. Furthermore, expression of the Mitf and Kcnd3 genes is activity-dependent in OB projection neurons and the MITF protein activates expression from Kcnd3 regulatory elements. Moreover, Mitf mutant mice have changes in olfactory habituation and have increased habitutation for an odourant following long-term exposure, indicating that regulation of Kcnd3 is pivotal for long-term olfactory adaptation. Our findings show that Mitf acts as a direct regulator of intrinsic homeostatic feedback and links neuronal activity, transcriptional changes and neuronal function. Significance statement These findings broaden the general understanding of transcriptional regulation of intrinsic plasticity in learning and memory. Regulation of intrinsic plasticity has wide-ranging implications and fundamental importance for neurological diseases.
: Microphthalmia-associated transcription factor (MITF) is a member of the basic helix-loop-helix leucine zipper (bHLH-Zip) family and functions as the master regulator of the melanocytic lineage. MITF-M is the predominant isoform expressed in melanocytes and melanoma cells, and, unlike other MITF isoforms, it is constitutively nuclear. Mutational analysis revealed three karyophilic signals in the bHLH-Zip domain of MITF-M, spanning residues 197-206, 214-217, and 255-265. Structural characteriza...
Summary Gene transcription is the process by which the genetic codes of organisms are read and interpreted as a set of instructions for cells to divide, differentiate, migrate, and mature. As cells function in their respective niches, transcription further allows mature cells to interact dynamically with their external environment while reliably retaining fundamental information about past experiences. In this Review, we provide an overview of the field of activity-dependent transcription in the...
The modification of synaptic strength produced by long-term potentiation (LTP) is widely thought to underlie memory storage. Indeed, given that hippocampal pyramidal neurons have >10,000 independently modifiable synapses, the potential for information storage by synaptic modification is enormous. However, recent work suggests that CREB-mediated global changes in neuronal excitability also play a critical role in memory formation. Because these global changes have a modest capacity for informatio...
Activity-dependent transcriptional responses shape cortical function. However, a comprehensive understanding of the diversity of these responses across the full range of cortical cell types, and how these changes contribute to neuronal plasticity and disease, is lacking. To investigate the breadth of transcriptional changes that occur across cell types in the mouse visual cortex after exposure to light, we applied high-throughput single-cell RNA sequencing. We identified significant and divergen...
Summary Enhancer elements are genomic regulatory sequences that direct the selective expression of genes so that genetically identical cells can differentiate and acquire the highly specialized forms and functions required to build a functioning animal. To differentiate, cells must select from among the ∼10 6 enhancers encoded in the genome the thousands of enhancers that drive the gene programs that impart their distinct features. We used a genetic approach to identify transcription factors (TF...
#2Dan Hasson(ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 16
Last. Emily Bernstein(ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 33
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Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a transmembrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apopto...
#2Nicolas Brunel(U of C: University of Chicago)H-Index: 60
Last. Christian Hansel(U of C: University of Chicago)H-Index: 32
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Synaptic plasticity (e.g., long-term potentiation [LTP]) is considered the cellular correlate of learning. Recent optogenetic studies on memory engram formation assign a critical role in learning to suprathreshold activation of neurons and their integration into active engrams ("engram cells"). Here we review evidence that ensemble integration may result from LTP but also from cell-autonomous changes in membrane excitability. We propose that synaptic plasticity determines synaptic connectivity m...
The highly specific organization of the olfactory bulb (OB) is well known, but the impact of early odorant experience on its circuit structure is unclear. Olfactory sensory neurons (OSNs) project axons from the olfactory epithelium to the OB, where they form spherical neuropil structures called glomeruli. These glomeruli and the postsynaptic targets of OSNs, including mitral and tufted cells (M/TCs) and juxtaglomerular cells, form glomerular modules, which represent the basic odor-coding units o...
The lining of the nose contains cells called olfactory sensory neurons that allow different smells to be detected. Odor molecules bind to receptor proteins that are embedded in the surface of the olfactory sensory neuron. Different receptors respond to different odors, and the nose contains hundreds of different receptors that work together to distinguish thousands of scents. When an odor molecule binds to a receptor, it triggers a pattern of electrical activity in the neuron. These patterns are...
#1J. David Sweatt(UAB: University of Alabama at Birmingham)H-Index: 98
This brief review summarizes 60 years of conceptual advances that have demonstrated a role for active changes in neuronal connectivity as a controller of behavior and behavioral change. Seminal studies in the first phase of the six-decade span of this review firmly established the cellular basis of behavior – a concept that we take for granted now, but which was an open question at the time. Hebbian plasticity, including long-term potentiation and long-term depression, was then discovered as bei...
#1Renata Santos(Salk Institute for Biological Studies)H-Index: 24
#2Sara B. Linker(Salk Institute for Biological Studies)H-Index: 10
Last. Fred H. Gage(Salk Institute for Biological Studies)H-Index: 237
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Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li-responsive (LR) and Li-non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on the LR neurons. In this study we sear...
The microphthalmia-associated transcription factor (MITF) is at the core of melanocyte and melanoma fate specification. The related factors TFEB and TFE3 have been shown to be instrumental for transcriptional regulation of genes involved in lysosome biogenesis and autophagy, cellular processes important for mediating nutrition signals and recycling of cellular materials, in many cell types. The MITF, TFEB, TFE3, and TFEC proteins are highly related. They share many structural and functional feat...
Abstract Isoforms play an essential role in enhancing evolutionary diversity. Microphthalmia inducing transcription factor (MITF) is known to be a master regulator of pigmentation response and a lineage survival oncogene in melanoma. MITF is also known to have several functional isoforms, the –M form is known to be essential for the melanocyte lineage and is the most widely studied in the context of pigmentation biology and melanoma development and progression. This study uses an RNA seq approac...
