Role of cell cycle dynamics in early cell fate decisions of interneuron precursors in the MGE
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
Interneurons play an essential role in the physiological function of the brain. The majority of forebrain interneurons are generated in the transient, embryonic ganglionic eminence (GE), with the medial GE (MGE) giving rise to biggest subclasses, the Parvalbumin (PV) and Somatostatin (SST) expressing interneurons. The imbalance of those subclasses can contribute to disorders like schizophrenia or autism spectrum disorders. Despite their importance, the cell fate determination of PV versus SST interneurons is still debated. This project elucidates 1) the genetic fingerprint driving the early PV versus SST cell fate decision and 2) how cell cycle dynamics play a role in those decisions. These aims are pursued using single cell RNA sequencing (scRNAseq) of MGE from genetically modified mice that manifest altered cell cycle dynamics at different developmental time points. The cell cycle regulator cyclin D2 (cD2), is known to be expressed in symmetrically dividing intermediate progenitors. Its knockout results in a disproportionate decrease in PV interneurons while the density of SST cells is unchanged in the forebrain of adult mice. The ablation of Partition defective (Pard) 3, crucial for the self-renewal of radial glia cells, in the MGE leads to a shift to the SST fate, while depleting the PV interneuron population. With these tools in hand, MGE progenitors of interneurons will be investigated during embryonic development, specifically at E11.5, E13.5 and E15.5. The preliminary analyses show a change in the developmental trajectory between the different cell types, suggesting that the PV vs. SST cell fate is already specified in proliferating progenitors. Together with Pard3, Pard6 and the atypical Protein Kinase C (aPKC) form the core apical polarity complex (APC). To investigate the cell cycle dynamics in neuronal progenitors, the interaction between cD2 and parts of the APC is analyzed. Due to breeding restriction during the COVID-19 pandemic, the focus was shifted from the cD2-Pard3 interaction to the phosphorylation of cD2 by aPKC and the impact on the progenitor populations of excitatory neurons in the cortex using in utero electroporation. Together, this project offers insights into the generation of PV and SST interneurons and illuminates a previously unappreciated interaction between key players of cell cycle dynamics, cD2 and the APC.
Publications
- Excitation/Inhibition Imbalance in Animal Models of Autism Spectrum Disorders. Biol. Psychiatry 2017; 81: 838–847
Lee E, Lee J, Kim E
(See online at https://doi.org/10.1016/j.biopsych.2016.05.011) - NMDAR hypofunction and somatostatin-expressing GABAergic interneurons and receptors: A newly identified correlation and its effects in schizophrenia. Schizophr. Res. Cogn. 2017; 8: 1–6
Alherz F, Alherz M, Almusawi H
(See online at https://doi.org/10.1016/j.scog.2017.02.001) - Parvalbumin and autism: different causes, same effect? Oncotarget 2017; 8: 7222–7223
Filice F, Schwaller B
(See online at https://dx.doi.org/10.18632%2Foncotarget.14238)
