Lhx2 and Lhx9 Determine Neuronal Differentiation and Compartition in the Caudal Forebrain by Regulating Wnt Signaling

Abstract

Initial axial patterning of the neural tube into forebrain, midbrain, and hindbrain primordia occurs during gastrulation. After this patterning phase, further diversification within the brain is thought to proceed largely independently in the different primordia. However, mechanisms that maintain the demarcation of brain subdivisions at later stages are poorly understood. In the alar plate of the caudal forebrain there are two principal units, the thalamus and the pretectum, each of which is a developmental compartment. Here we show that proper neuronal differentiation of the thalamus requires Lhx2 and Lhx9 function. In Lhx2/Lhx9-deficient zebrafish embryos the differentiation process is blocked and the dorsally adjacent Wnt positive epithalamus expands into the thalamus. This leads to an upregulation of Wnt signaling in the caudal forebrain. Lack of Lhx2/Lhx9 function as well as increased Wnt signaling alter the expression of the thalamus specific cell adhesion factor pcdh10b and lead subsequently to a striking anterior-posterior disorganization of the caudal forebrain. We therefore suggest that after initial neural tube patterning, neurogenesis within a brain compartment influences the integrity of the neuronal progenitor pool and border formation of a neuromeric compartment.

Evolutionarily conserved regulation of hypocretin neuron specification by Lhx9

“…However, the developmental roles of specific LIM homeobox genes have been difficult to distinguish; loss-of-function phenotypes are subtle and similar LIM homeobox family members often exhibit redundancy. For instance, double knockdown of lhx9 and lhx2 dramatically altered thalamus and forebrain patterning in zebrafish, but knockdown of either gene alone had no gross effects (Peukert et al, 2011). Similarly, Lhx9 knockout mice survive to adulthood without gross brain defects (Birk et al, 2000).…”

“…Since the expression patterns of hcrt and lhx9 are conserved between zebrafish and mammals (Peukert et al, 2011;Shimogori et al, 2010), we tested whether Lhx9 overexpression could induce Hcrt neuron specification in mice. Indeed, Lhx9 overexpression by in utero electroporation was sufficient to specify additional Hcrt neurons, although they were only observed in the endogenous Hcrt neuron domain.…”

Development of the hypothalamus: conservation, modification and innovation

“…Indeed, when Tcf7l1, which encodes a transcriptional repressor of Wnt targets, is conditionally knocked out in the mouse hypothalamus and pituitary, the developing hypothalamus is posteriorized (Gaston-Massuet et al, 2016). Lhx2, a potential upstream inhibitor of Wnt signaling (Peukert et al, 2011), has also been shown to play a role in the patterning of the telencephalicoptic-hypothalamic field, and to specify SCN neurons at the expense of neuroendocrine fates (Roy et al, 2013).…”

The LIM and POU homeobox genes ttx-3 and unc-86 act as terminal selectors in distinct cholinergic and serotonergic neuron types

“…We focus here on the ttx-3 LIM homeobox gene, which is the sole C. elegans member of the Lhx2/9 subclass of LIM homeobox genes. In vertebrates, Lhx2 is expressed in multiple neuronal cell types and is required for the differentiation of olfactory sensory neurons (Hirota and Mombaerts, 2004;Kolterud et al, 2004), the specification of cortical neuron fate (Mangale et al, 2008) and the differentiation of thalamic neurons (Peukert et al, 2011). Whether there is a common theme in the function of Lhx2 in these distinct neuronal cell types is not known.…”