Helios expression coordinates the development of a subset of striatopallidal medium spiny neurons.

Raquel Martín-Ibáñez,Cristina Herranz,Andrés Miguez,Lucile Marion-Poll,Michael J Edel,Susan Chan,Philippe Kastner,Albert Giralt,Mónica Pardo,Miriam Esgleas,Gerardo Garcia-Díaz Barriga,Josep M Canals,Inés Guardia,Carlos Vicario-Abejón,Jean-Antoine Girault,Jordi Alberch

doi:10.1242/dev.138248

Abstract

Here, we unravel the mechanism of action of the Ikaros family zinc finger protein Helios (He) during the development of striatal medium spiny neurons (MSNs). He regulates the second wave of striatal neurogenesis involved in the generation of striatopallidal neurons, which express dopamine 2 receptor and enkephalin. To exert this effect, He is expressed in neural progenitor cells (NPCs) keeping them in the G1/G0 phase of the cell cycle. Thus, a lack of He results in an increase of S-phase entry and S-phase length of NPCs, which in turn impairs striatal neurogenesis and produces an accumulation of the number of cycling NPCs in the germinal zone (GZ), which end up dying at postnatal stages. Therefore, He−/− mice show a reduction in the number of dorso-medial striatal MSNs in the adult that produces deficits in motor skills acquisition. In addition, overexpression of He in NPCs induces misexpression of DARPP-32 when transplanted in mouse striatum. These findings demonstrate that He is involved in the correct development of a subset of striatopallidal MSNs and reveal new cellular mechanisms for neuronal development.

Highlights

The mammalian striatum controls body movements through a sophisticated neuronal network that is dependent on the neurogenesis of two major classes of striatal neurons: the striatal projection neurons and the interneurons
Between He and short-pulsed BrdU neural progenitor cells (NPCs) (Fig. 2E,F), and He and phospho-histone H3 (PH3)+ NPCs (Fig. 2G,H). He only colocalized with Ki67-expressing cells during the neurogenic period as we could not observe colocalization from E18.5 onwards (Fig. S6). He loss induces aberrant striatal neurogenesis accompanied by de-regulation of NPC proliferation
We demonstrated that He is expressed from E12.5 in scattered cells (Fig. S1) until P15 peaking at E18.5 (Martín-Ibáñez et al, 2012). He showed preferential expression in D2R-eGFP neurons and Penk+ medium spiny neurons (MSNs) (89.05 ±5.77% of He+ cells co-labeled with Penk; Fig. S3)

Summary

Introduction

The mammalian striatum controls body movements through a sophisticated neuronal network that is dependent on the neurogenesis of two major classes of striatal neurons: the striatal projection neurons (or medium spiny neurons; MSNs) and the interneurons. MSNs are subdivided into two subpopulations: neurons that constitute the direct (or striatonigral) pathway and preferentially express substance P (SP) and D1R (dopamine receptor 1; DRD1), and neurons of the indirect (or striatopallidal) pathway, which mainly express enkephalin (ENK) and D2R (dopamine receptor 2; DRD2) (Gerfen, 1992). These two populations are differentially distributed within the striatal compartments. Two waves of striatal neurogenesis segregate MSNs into two principal compartments: the patches, generated during the first neurogenic wave [starting at embryonic day (E) 12.5 in mouse]; and the matrix, developed during late striatal neurogenesis (starting at E14.5 in mouse) (Gerfen, 1992; Mason et al, 2005)

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Conclusion