Transcription factor Lhx2 is necessary and sufficient to suppress astrogliogenesis and promote neurogenesis in the developing hippocampus

Abstract

The sequential production of neurons and astrocytes from neuroepithelial precursors is a fundamental feature of central nervous system development. We report that LIM-homeodomain (LIM-HD) transcription factor Lhx2 regulates this transition in the developing hippocampus. Disrupting Lhx2 function in the embryonic hippocampus by in utero electroporation and in organotypic slice culture caused the premature production of astrocytes at stages when neurons are normally generated. Lhx2 function is therefore necessary to suppress astrogliogenesis during the neurogenic period. Furthermore, Lhx2 overexpression was sufficient to suppress astrogliogenesis and prolong the neurogenic period. We provide evidence that Lhx2 overexpression can counteract the instructive astrogliogenic effect of Notch activation. Lhx2 overexpression was also able to override and suppress the activation of the GFAP promoter by Nfia, a Notch-regulated transcription factor that is required for gliogenesis. Thus, Lhx2 appears to act as a "brake" on Notch/Nfia-mediated astrogliogenesis. This critical role for Lhx2 is spatially restricted to the hippocampus, because loss of Lhx2 function in the neocortex did not result in premature astrogliogenesis at the expense of neurogenesis. Our results therefore place Lhx2 as a central regulator of the neuron-glia cell fate decision in the hippocampus and reveal a striking regional specificity of this fundamental function within the dorsal telencephalon.

Multiple intrinsic factors act in concert with Lhx2 to direct retinal gliogenesis

“…Previous studies observed that endogenous expression of Lhx2 in hippocampal progenitor cells may override the gliogenic activity of Nfia , and that misexpression of Nfia with concurrent Lhx2 loss of function promoted hippocampal astrogliogenesis34. We tested whether Nfia was sufficient to promote MG development with Lhx2 loss of function by electroporating Nfia/Cre into Lhx2 lox/lox mice.…”

“…Electroporation of Sox2/Cre and Sox9/Cre both significantly boosted amacrine cell numbers in Lhx2 lox/lox mice compared to electroporation of Cre alone. This suggests that in addition to being necessary for retinal gliogenesis, Lhx2 may also play a more general role in modulating and constraining levels of neurogenesis in late-stage RPCs, as has been described in the cortex and hippocampus344849. Whether this modulation is achieved indirectly through regulation of Notch or directly through competition and interaction at common target loci is unclear.…”

Seizure evoked regulation of LIM-HD genes and co-factors in the postnatal and adult hippocampus

“…Members of the LIM-HD family of transcription factors are necessary for different aspects of the development of the hippocampus 11, 18, 19 , a structure that is vulnerable to changes in response to activity. LIM genes are differentially expressed in both the postnatal and adult hippocampus, suggesting that there might be a role for these genes in postnatal circuit development and adult reorganization 16 .…”

Organotypic Explants of the Embryonic Rodent Hippocampus: An Accessible System for Transgenesis

“…The example shown below is E15.5 from a Swiss mouse. Nfia mutant embryos which were on the C57BL/6J background have also been used successfully in Subramanian et al , 2011.…”

“…Scale bar = 100 μm. This figure and legend are modified from Figure 5, Subramanian et al ., PNAS, 2011.…”