The LIM-homeobox gene Lhx8 is required for the development of many cholinergic neurons in the mouse forebrain

Abstract

Forebrain cholinergic neurons play important roles as striatal local circuit neurons and basal telencephalic projection neurons. The genetic mechanisms that control development of these neurons suggest that most of them are derived from the basal telencephalon where Lhx8, a LIM-homeobox gene, is expressed. Here we report that mice with a null mutation of Lhx8 are deficient in the development of forebrain cholinergic neurons. Lhx8 mutants lack the nucleus basalis, a major source of the cholinergic input to the cerebral cortex. In addition, the number of cholinergic neurons is reduced in several other areas of the subcortical forebrain in Lhx8 mutants, including the caudate-putamen, medial septal nucleus, nucleus of the diagonal band, and magnocellular preoptic nucleus. Although cholinergic neurons are not formed, initial steps in their specification appear to be preserved, as indicated by a presence of cells expressing a truncated Lhx8 mRNA and mRNA of the homeobox gene Gbx1. These results provide genetic evidence supporting an important role for Lhx8 in development of cholinergic neurons in the forebrain.T he mammalian forebrain contains two general types of cholinergic neurons. One group is composed of local circuit neurons, such as the cholinergic interneurons of the striatum (1). These neurons play an important role in the regulation of locomotor behavior through their modulation of ␥-aminobutyric acid (GABA)ergic projection neurons in the striatum (2). The other group consists of projection neurons whose cell bodies can be found in a series of nuclei in the subcortical telencephalon, including the medial septum (also designated as Ch1 cholinergic group by Mesulam et al., ref. 3), the vertical and horizontal limbs of the nucleus of the diagonal band (designated as Ch2 and Ch3, respectively; ref.3), and the basal magnocellular complex (designated as Ch4; ref.3), which comprises cholinergic neurons scattered through the magnocellular preoptic nucleus, substantia innominata, ventral pallidum, and nucleus basalis. The axonal projections of these neurons provide the cerebral cortex and hippocampus with their principal cholinergic input (3-6), which has a critical role in cognitive functions (for reviews, see refs. 7 and 8). Accordingly, abnormalities of the cholinergic projection neurons in the basal forebrain are implicated in neurodegenerative disorders such as Alzheimer's disease (9, 10).The genetic and developmental mechanisms that control the formation of forebrain cholinergic neurons are just beginning to be elucidated. The vast majority of forebrain cholinergic neurons derive from a region of the subcortical telencephalon that expresses the Nkx2-1 homeobox gene (11,12). This region contains different progenitor zones, including the medial ganglionic eminence (MGE), anterior entopeduncular area and preoptic area (POa) (13). It has been proposed that these progenitor domains contribute projection neurons to the globus pallidus, ventral pallidum, nucleus of the diagonal band, and parts of the septum and amygd...

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

“…S1D) and CSIs were dramatically reduced in the striatum (Fig. S1 E-G) (8,(12)(13)(14). Interestingly, reduction of CSIs was associated with increased number of Lhx6-expressing striatal interneurons (Fig.…”

“…Interestingly, reduction of CSIs was associated with increased number of Lhx6-expressing striatal interneurons (Fig. S1F), a characteristic feature of Lhx7-null mice (8,(12)(13)(14). Therefore, upon Cre-mediated recombination, Lhx7 fl is converted into a null allele.…”

“…"Terminal selector genes" encode transcription factors that coordinately regulate the expression of diverse molecular, morphological and functional characteristics that constitute the terminal phenotype of neurons (23). Lhx7 and Lhx6 belong to this class of genes because, respectively, they regulate multiple aspects of cholinergic and GABAergic interneuron differentiation in the mammalian forebrain (8,10,(12)(13)(14). In vertebrates terminal selector genes have been studied mostly in the context of lineage restriction and forward neuronal differentiation, but their subsequent role in maintaining neuronal subtype identity is largely unknown.…”

“…In contrast, Lhx6 is undetectable in CSIs, which invariably coexpress Isl1 and Lhx7. Genetic studies have established the requirement of Lhx7 and Isl1 for the specification of forebrain cholinergic neurons (11)(12)(13)(14), but the potential role of these factors in maintaining the identity of CSIs following their specification and differentiation is currently unknown.…”

Cholinergic Circuits and Signaling in the Pathophysiology of Schizophrenia

“…In particular, the basics of a cholinergic transcription factor code are emerging. A variety of experimental approaches has demonstrated that expression of several transcription factors is important (Mash 1, Olig2, Lmx7, Lmx8) or essential (Nkx2.1) for generating forebrain cholinergic neurons (Bachy and Retaux, 2006;Furusho et al, 2006;Marin et al, 2000;Mori et al, 2004;Zhao et al, 2003). Thus, the combined expression of these factors, and their target genes, probably accounts for much of the intrinsic identity of the cholinergic phenotype.…”