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

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.

Alpha2-Containing Glycine Receptors Promote Neonatal Spontaneous Activity of Striatal Medium Spiny Neurons and Support Maturation of Glutamatergic Inputs

“…At the age of 6–7 days, roughly 30% of striatal MSNs are spontaneously firing APs, which is in the accordance with previous findings ( Dehorter et al, 2011 ). During development, MSNs are generated by two waves of neurogenesis, separated by 2 days in mice ( Passante et al, 2008 ; Martin-Ibanez et al, 2017 ). This time gap persists during the postnatal development, and gives rise to two principal striatal compartments: patches and matrix ( Brimblecombe and Cragg, 2017 ).…”

Radial glia in the ventral telencephalon

“…Changes in cell-cycle parameters have significant effects on the cellular output from subpallial progenitors: in the MGE, the loss of G1/S-phase-specific cyclin D2 in the MGE decreases SVZ proliferation and increases cell cycle exit, causing a reduction in the number of a subgroup of late-born cortical interneurons (parvalbumin-positive: see below) [38]. Likewise, the length of S phase of LGE progenitors is decreased as they undergo a major developmental transition late in striatal neurogenesis, switching from producing striatonigral to striatopallidal medium spiny neurons [39]. These findings suggest that cell-cycle regulation is important for the proliferation and differentiation of subpallial progenitors [40], and highlight the need for further studies taking into account the diversity of germinal zones and progenitor types in the subpallium.…”

“…Isl1 and Sp9 appear to be differentially expressed in the early-born striatonigral and late-born striatopallidal lineages, respectively [108,109]. The zinc-finger protein Helios controls the transition of LGE progenitors through the production of these two lineages [39]. The dorsal portion of the LGE (dLGE) lies immediately adjacent to the cortex, ventral to the pallial-subpallial boundary, and is characterized by expression of Gsx2, Er81, and low levels of Pax6.…”

Active intermixing of indirect and direct neurons builds the striatal mosaic

“…SPN are generated in the embryonic lateral ganglionic eminence (LGE) and migrate radially to form the striatum [18][19][20][21][22][23][24] . Both SPN subtypes are present in the entire striatum, except for a restricted caudal domain 8 , and several transcription factors have been involved in their generation and differentiation including Ctip2, FoxP1 and FoxP2 [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] . In addition, distinct transcriptomic programs have been involved in the specification of either dSPN or iSPN, including Islet1 and Ebf1 for dSPN or Sp9 and Six3 for iSPN 23,[41][42][43][44][45][46] .…”