Team 7 – Molecular Biology of Neuronal Transport
(coming soon)

The team is expected to start by the end of 2022. If you are motivated and would like to discuss the possibility of joining our projects either as a postdoc, PhD/Master student, or Technician/Assistant Engineer, please contact me at nicolas.panayotis@weizmann.ac.il.

The importin family of nuclear import factors have pivotal roles in the subcellular transport of proteins from the cytoplasm and the synapse to the nucleus (Panayotis et al., 2015). While huge efforts helped to decipher the basic elements and properties of the nuclear transport, including the importin families of nuclear transport carriers (Schmidt and Gorlich, 2016), little attention has been paid to the roles of importins in the regulation of CNS functions. In recent years, several studies, showed that importins have pivotal roles in the neuronal and nuclear transport of macromolecules during synaptic plasticity, maintenance, survival, and regeneration (Panayotis et al., 2015; Rishal and Fainzilber, 2014).

The mission of our team is to determine the roles of importins nuclear transport factors in neuronal functions and neurodevelopmental disorders (NDDs), and to define the mechanistic rules of importin-mediated transport in physiologically-relevant networks. This approach will provide news findings and, importantly, news targets for therapeutic intervention in most often intractable neurological conditions.

1. Importins are Important for CNS functions

Using a battery of approaches from behavior to molecular mechanisms, we discovered the role of importin α5 in anxiety pathways by regulating MeCP2 nuclear import in hippocampal neurons (Panayotis et al., 2018) and the role of importin α3 in the transport of c-Fos in dorsal root ganglia (DRG) neurons during chronic pain (Marvaldi et al., 2020).

Our team at the SPPIN is exploring the phenotypes of several importin mutant mice. This approach will help us to dissect out the precise locus of the importin α5-anxiolysis. In addition, our previous analyses also revealed phenotypes affecting functions such as motor coordination, social dominance, and spatial memory. In-depth analyses of these different models will be carried using advanced imaging, RNA-seq and translatomics, in cell and animal models. This research is expected to generate exciting insights on importin control of transcription and neuropathological mechanisms.

2. Control of Transcription Factors Nuclear Import & Biology

We identified two functionally relevant importin-TF interacting pairs (α5-MeCP2 and α3-c-Fos). However, to date, the transport mechanisms controlling the abundance of TFs in the nucleus, and the transcriptional pathways at the core of NDDs, have not been targeted in a systematic manner. Thus, our second aim is to study the role of nuclear transport factors in neurogenetic brain disorders. Given the key role of MeCP2 in gene expression, both Rett syndrome (RTT) and MeCP2 fields tackled questions fundamental to the understanding of neuronal functions, gene expression, and brain disorders. MeCP2 mutations cause RTT, a devastating and progressive neuropathology while MeCP2 duplications cause severe cases of intellectual disabilities.

Our priority is to dissect the basic rules of importin α-MeCP2’s interaction and transport dynamics using behavioral analyses, live imaging of MeCP2 nuclear shuttling, and testing how modulation of MeCP2 transport can rescue phenotypes associated with MeCP2-related disorders such as Rett and MeCP2 duplication syndromes (Lombardi et al., 2015; Lyst and Bird, 2015). We will then expand the study to additional TFs and cellular/mouse models of genetic disorders.

3. New Molecular Tools to Control & Study the Nuclear Transport

Our group is motivated to develop light-sensitive systems in order to control the nuclear import/export (Karasev et al., 2022; Niopek et al., 2014; Rost et al., 2017) of TFs in neuronal cells. At term, these efforts will shed light on basic principles that will allow us to modulate the nuclear levels of a broad range of TFs including MeCP2, c-Fos, and other TFs to be identified from the screens of importin mutant mice described above.

4. Harnessing RNA-seq data to discover new CNS drugs

As demonstrated in our recent works (Marvaldi et al., 2020; Panayotis et al., 2021), the proposed research will also make the most of RNA-seq and in silico approaches to screen drugs that can present new therapeutics properties.

The translational aspect of our research will allow us to make the most of molecular neurobiology and neurogenetics approaches to discover new therapeutic avenues and ameliorate devastating human disorders.

Team leader

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