Helt determines GABAergic over glutamatergic neuronal fate by repressing Ngn genes in the developing mesencephalon

The generation and maintenance of a plethora of neuronal subtypes is essential for normal brain function. Nevertheless, little is known about the molecular mechanisms that maintain the defining characteristics of neurons following their initial postmitotic specification. Using conditional gene ablation in mice, we demonstrate here that the homeodomain protein LIM homeobox (Lhx)7 is essential for maintaining the morphological and molecular characteristics of cholinergic interneurons of the striatum. Lhx7-depleted cholinergic interneurons extinguish expression of several subtype-specific markers, including choline acetyl transferase and Isl1, and are respecified into Lhx6-expressing mature GABAergic interneurons. Additional expression studies support a model where Lhx7 controls the choice between cholinergic or GABAergic identity by gating a cross inhibitory regulation between Isl1 and Lhx6. By demonstrating that the switch between alternative striatal interneuron fates depends on persistent activity of a single transcription factor, we provide evidence that the intrinsic plasticity of mammalian forebrain neuronal subtypes is maintained after the initial specification and lineage commitment and possibly throughout life.neuronal subtype specification | medial ganglionic eminence-derived interneurons T he information-processing ability of the nervous system depends on the formation of functional neuronal circuits composed of a highly heterogeneous population of neurons. Recent progress has identified molecular cascades that control the generation of distinct neuronal subtypes during development (1-3) but the mechanisms that maintain the identity of neurons following lineage commitment and differentiation are currently unclear. Identifying such mechanisms is critical for understanding phenotypic plasticity in the nervous system and, ultimately, influencing its ability to adjust during normal development, disease, or injury.The striatum is a subcortical structure that integrates multiple inputs from the cortex, thalamus, and midbrain and relays information to the output domains of the basal ganglia via its principal population of projection neurons (4, 5). Balanced striatal output, which is critical for motor and cognitive activity, depends on local circuits controlled by distinct subpopulations of GABAergic and cholinergic interneurons (5). Both GABAergic and cholinergic striatal interneurons (GSIs and CSIs, respectively) are derived from Nkx2.1-expressing progenitors of the medial ganglionic eminence (MGE) (6, 7), which, upon exit from the cell cycle, express the LIM homeodomain (LIM HD) transcription factors LIM homeobox 6 (Lhx6) and LIM homeobox 7 (Lhx7) (8). A subset of these precursors maintains expression of Lhx6 and differentiate into mature GABAergic interneurons expressing the neuropeptide somatostatin (Sst) or the calcium-binding protein parvalbumin (Pv) (9, 10). The remaining precursors induce expression of the LIM HD protein Isl1, down-regulate Lhx6, and differentiate into CSIs (8). In adult animals, all ...

Section: Discussionmentioning

confidence: 99%

Transcription factor LIM homeobox 7 (Lhx7) maintains subtype identity of cholinergic interneurons in the mammalian striatum

Lopes

Wijk

Neves

et al. 2012

“…Because the RN was prominent in our fate map (Fig. 1B), we tested whether these neurons may originate in the lateral aspects of the Shh domain, by double labeling with Brn3a, a marker for these neurons (21)(22)(23). Indeed, a ␤-galϩ/Brn3aϩ cohort was observed emanating from lateral ␤-galϩ progenitors ( Fig.…”

Section: Shh Expressing Progenitors Give Rise To Multiple Neuron Typementioning

confidence: 99%

Spatiotemporally separable Shh domains in the midbrain define distinct dopaminergic progenitor pools

Joksimovic

Anderegg

Roy

et al. 2009

108

121

Midbrain dopamine neurons (mDA) are important regulators of diverse physiological functions, including movement, attention, and reward behaviors. Accordingly, aberrant function of dopamine neurons underlies a wide spectrum of disorders, such as Parkinson's disease (PD), dystonia, and schizophrenia. The distinct functions of the dopamine system are carried out by neuroanatomically discrete subgroups of dopamine neurons, which differ in gene expression, axonal projections, and susceptibility in PD. The developmental underpinnings of this heterogeneity are undefined. We have recently shown that in the embryonic CNS, mDA originate from the midbrain floor plate, a ventral midline structure that is operationally defined by the expression of the molecule Shh. Here, we develop these findings to reveal that in the embryonic midbrain, the spatiotemporally dynamic Shh domain defines multiple progenitor pools. We deduce 3 distinct progenitor pools, medial, intermediate, and lateral, which contribute to different mDA clusters. The earliest progenitors to express Shh, here referred to as the medial pool, contributes neurons to the rostral linear nucleus and mDA of the ventral tegmental area/interfascicular regions, but remarkably, little to the substantia nigra pars compacta. The intermediate Shh؉ progenitors give rise to neurons of all dopaminergic nuclei, including the SNpc. The last and lateral pool of Shh؉ progenitors generates a cohort that populates the red nucleus, Edinger Westphal nucleus, and supraoculomotor nucleus and cap. Subsequently, these lateral Shh؉ progenitors produce mDA. This refined ontogenetic definition will expand understanding of dopamine neuron biology and selective susceptibility, and will impact stem cell-derived therapies and models for PD.dopamine ͉ Sonic hedgehog ͉ lineage ͉ substantia nigra

“…Do neuronal terminal selector gene exist in more complex nervous systems as well? The selector gene concept has already been applied to TFs acting in neuronal specification in flies and vertebrates (24,(26)(27)(28)(29)), yet it is not known whether in those cases the respective TF is truly a terminal selector gene that directly acts on terminal differentiation gene batteries. Terminal differentiation gene batteries that define individual neuron types are beginning to be identified in vertebrates by using transcriptome analysis from isolated cells (30).…”

Section: Terminal Selector Genes and Terminal Selector Motifsmentioning

confidence: 99%

Regulatory logic of neuronal diversity: Terminal selector genes and selector motifs

Hobert

2008

263

284

Individual neuronal cell types are defined by the expression of unique batteries of terminal differentiation genes. The elucidation of the cis-regulatory architecture of several distinct, single neuron type-specific gene batteries in Caenorhabditis elegans has revealed a strikingly simple cis-regulatory logic, in which small cis-regulatory motifs are activated in postmitotic neurons by autoregulating transcription factors (TFs). Loss of the TFs results in the loss of the identity of the individual neuron type. I propose to term these TFs ''terminal selector genes'' and their cognate cis-regulatory target sites ''terminal selector motifs.'' Terminal selector genes assign individual neuronal identities by directly controlling the expression of downstream, terminal differentiation genes and act in specific regulatory network configurations. The simplicity of the cis-regulatory logic on which the terminal selector gene concept is based may contribute to the evolvability of neuronal diversity.