Unipolar (Dendritic) Brush Cells Are Morphologically Complex and Require Tbr2 for Differentiation and Migration.

Ashley Mcdonough,Robert F Hevner,Amelia R Bachleda,Olivia M Delletorri,Donald Pizzo,Ray M Daza,Gina E Elsen

doi:10.3389/fnins.2020.598548

Abstract

Previous studies demonstrated specific expression of transcription factor Tbr2 in unipolar brush cells (UBCs) of the cerebellum during development and adulthood. To further study UBCs and the role of Tbr2 in their development we examined UBC morphology in transgenic mouse lines (reporter and lineage tracer) and also examined the effects of Tbr2 deficiency in Tbr2 (MGI: Eomes) conditional knock-out (cKO) mice. In Tbr2 reporter and lineage tracer cerebellum, UBCs exhibited more complex morphologies than previously reported including multiple dendrites, bifurcating dendrites, and up to four dendritic brushes. We propose that “dendritic brush cells” (DBCs) may be a more apt nomenclature. In Tbr2 cKO cerebellum, mature UBCs were completely absent. Migration of UBC precursors from rhombic lip to cerebellar cortex and other nuclei was impaired in Tbr2 cKO mice. Our results indicate that UBC migration and differentiation are sensitive to Tbr2 deficiency. To investigate whether UBCs develop similarly in humans as in rodents, we studied Tbr2 expression in mid-gestational human cerebellum. Remarkably, Tbr2+ UBC precursors migrate along the same pathways in humans as in rodent cerebellum and disperse to create the same “fountain-like” appearance characteristic of UBCs exiting the rhombic lip.

Highlights

Unipolar brush cells (UBCs) are a type of glutamatergic interneuron localized to the granule cell layer of the cerebellum and are especially abundant in the posterior vermis (Floris et al, 1994; Dino et al, 1999; Nunzi et al, 2001; Kalinichenko and Okhotin, 2005; Mugnaini et al, 2011)
To determine if Tbr2 is necessary for the development of unipolar brush cell (UBC) we examined Tbr2 conditional knock-out (cKO) mice
We found that UBCs are absent from the Tbr2 cKO cerebellum as determined by immunohistochemistry (IHC) for markers of all UBC subtypes

Summary

INTRODUCTION

Unipolar brush cells (UBCs) are a type of glutamatergic interneuron localized to the granule cell layer of the cerebellum and are especially abundant in the posterior vermis (Floris et al, 1994; Dino et al, 1999; Nunzi et al, 2001; Kalinichenko and Okhotin, 2005; Mugnaini et al, 2011). In the embryonic cerebellum there are distinct progenitor compartments that produce GABAergic and glutamatergic neurons The former originate from the ventricular zone (VZ) of the fourth ventricle, while the latter are generated from the rhombic lip (Englund et al, 2006; Fink et al, 2006; Millen and Gleeson, 2008). UBCs migrate from the rhombic lip through developing white matter to cerebellar cortex and to the dorsal cochlear nucleus producing a "fountain-like" migration in sagittal histological sections (Englund et al, 2006). This includes novel UBC morphologies with multiple brushes suggesting that UBCs are more complex than previously thought

Experimental Procedures

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CONCLUSION

ETHICS STATEMENT