The LIM homeobox gene, L3/Lhx8, is necessary for proper development of basal forebrain cholinergic neurons

Abstract

Basal forebrain cholinergic neurons (BFCNs) are involved in cognitive functions such as learning and memory, and are affected in several neurodegenerative diseases (e.g. Alzheimer's disease). Despite their importance, the molecular mechanisms of their development are not fully elucidated. A recent report demonstrated that some BFCNs in adult rat are positive for L3/Lhx8, a LIM homeobox transcription factor. To examine the function of L3/Lhx8 in the development of BFCNs, we generated L3/Lhx8 gene-disrupted mice. In these mice, cells expressing cholinergic neuron markers, such as choline acetyltransferase, vesicular acetylcholine transporter and p75 low-affinity NGF receptor, were markedly reduced in the basal forebrain, whereas other cholinergic neurons including brain stem and spinal motor neurons expressed the markers. Neurotransmitter phenotypes other than cholinergic in the basal forebrain appeared intact. From these results, we suggested that L3/Lhx8 has a pivotal and specific role in the development and/or maintenance of BFCNs.

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

“…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.…”

“…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.…”

“…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.…”