Lhx6 and Lhx8: cell fate regulators and beyond

Abstract

As transcription factors of the lines (LIN)-11/Islet (Isl)-1/mitosis entry checkpoint (MEC)-3 (LIM)-homeobox subfamily, LIM homeobox (Lhx)6 and -8 are remarkably conserved and involved in the morphogenesis of multiple organ systems. Lhx6 and -8 play overlapping and distinctive roles, but in general act as cell fate mediators and in turn are regulated by several transcriptional factors, such as sonic hedgehog, fibroblast growth factors, and wingless-int (Wnt)/β-catenin. In this review, we first summarize Lhx6 and -8 distributions in development and then explore how Lhx6 and -8 act as transcription factors and coregulators of cell lineage specification. Known Lhx6 and -8 functions and targets are outlined in neurogenesis, craniofacial development, and germ cell differentiation. The underlying mechanisms of Lhx6 and -8 in regulating cell fate remain elusive. Whether Lhx6 and -8 affect functions in tissues and organs other than neural, craniofacial, oocytes, and germ cells is largely unexplored. Taken together, Lhx6 and -8 are important regulators of cell lineage specification and may act as one of the pivotal mediators of stem cell fate. Undoubtedly, future investigations of Lhx6 and -8 biology will continue to yield fascinating insights into tissue development and homeostasis, in addition to their putative roles in tissue regeneration and ageing.

Keywords: LIM homeobox genes; neurogenesis; palatogenesis; tooth development; transcriptional regulation.

Figure 1.

In situ hybridization of Lhx8 expression during mouse development. Lhx8 expression in the central nervous system was restricted to MGE of basal forebrain at E12.5 (A) and E14.5 (B) mouse embryo. C) During tooth morphogenesis, Lhx8 expression was detected primarily in BA1 at E11.5 by wholemount in situ hybridization. D, E) Lhx8 was further detected in neural crest–derived mesenchyme and was especially robust in the dental mesenchyme at E14.5 (cap stage). F) Lhx8 mRNA was restricted postnatally in the odontoblast layer. am, ameloblast; d, dentin; de, dental epithelium; dm, dental mesenchyme; mc, Meckel’s cartilage; md, mandibular process; mn, medial nasal process; mx, maxillary process; od, odontoblast; oe, oral epithelium; p, palate. Scale bars, 200 µm.

Figure 2.

Lhx families function through protein–protein interactions. The N-terminal region of Ldb mediates the dimerization, whereas the C-terminal region mediates the interactions between dimerized Lhx proteins that are the same (A) or different (B) through LIM domains. C) Lhx proteins can also interact with RLIM through the LIM domain, which in turn recruits Sin3A or other epigenetic regulators.

Figure 3.

Lhx6 and -8 in neurogenesis. Neurogenesis-related transcription factor NKx2-1 upregulates Lhx6 and -8. Lhx8 together with Lhx6 promotes GABAergic neuron differentiation, whereas Lhx8 together with Isl1 favors cholinergic differentiation mediated by Shh, ChAT, and LNGFR.

Figure 4.

Critical roles of Lhx6 and -8 in epithelium–mesenchyme crosstalk. Epithelium-derived FGF8 and TGF-β3 bind to their receptors in the underlying mesenchyme, resulting in the upregulation of Lhx6 and -8. Lhx8, together with Lhx6, is involved in odontogenesis through regulating Msx1, Msx2, Bmp4, Gsc, and others.