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In the developing central nervous system, transcription factors play a crucial role in the regulation of cell fate. Previously we demonstrated that LHX2 is a critical regulator of the neuron-glia cell fate switch in the developing mouse hippocampus. Here, we test LHX2 target gene Pax6 for a role in this process. We report that Pax6 overexpression is able to suppress the enhanced astrogliogenesis arising due to loss of functional LHX2. Furthermore, we show that like Lhx2, Pax6 is also able to suppress induced astrogliogenesis caused by overexpression of progliogenic factor Nfia. This demonstrates that overexpression of Pax6 can substitute for Lhx2 in the regulation of the neuronal versus glial cell fate in the developing hippocampus, and therefore, supports a role for PAX6 as a mediator of LHX2 function in this process.

Regulation of the neuron-glia cell-fate switch is a critical step in the development of the CNS. Previously, we demonstrated that Lhx2 is a necessary and sufficient regulator of this process in the mouse hippocampal primordium, such that Lhx2 overexpression promotes neurogenesis and suppresses gliogenesis, whereas loss of Lhx2 has the opposite effect.Wetested a series of transcription factors for their ability to mimic Lhx2 overexpression and suppress baseline gliogenesis, and also to compensate for loss of Lhx2 and suppress the resulting enhanced level of gliogenesis in the hippocampus. Here, we demonstrate a novel function of Dmrt5/Dmrta2 as a neurogenic factor in the developing hippocampus. We show that Dmrt5, as well as known neurogenic factors Neurog2 and Pax6, can each not only mimic Lhx2 overexpression, but also can compensate for loss of Lhx2 to different extents. We further uncover a reciprocal regulatory relationship between Dmrt5 and Lhx2, such that each can compensate for loss of the other. Dmrt5 and Lhx2 also have opposing regulatory control on Pax6 and Neurog2, indicating a complex bidirectionally regulated network that controls the neuron-glia cell-fate switch. Finally, we confirm that Lhx2 binds a highly conserved putative enhancer of Dmrt5, suggesting an evolutionarily conserved regulatory relationship between these factors. Our findings uncover a complex network that involves Lhx2, Dmrt5, Neurog2, and Pax6, and that ensures the appropriate amount and timing of neurogenesis and gliogenesis in the developing hippocampus.Significance Statement Weidentify Dmrt5 as a novel regulator of the neuronglia cell-fate switch in the developing hippocampus.Wedemonstrate Dmrt5 to be neurogenic, and reciprocally regulated by Lhx2: loss of either factor promotes gliogenesis; overexpression of either factor suppresses gliogenesis and promotes neurogenesis; each can substitute for loss of the other. Furthermore, each factor has opposing effects on established neurogenic genes Neurog2 and Pax6. Dmrt5 is known to suppress their expression, and we show that Lhx2 is required to maintain it. Our study reveals a complex regulatory network with bidirectional control of a fundamental feature of CNS development, the control of the production of neurons versus astroglia in the developing hippocampus., SCOPUS: ar.j, info:eu-repo/semantics/published

LIM domain binding protein 1 (LDB1) is a protein cofactor that participates in several multiprotein complexes with transcription factors that regulate mouse forebrain development. SinceLdb1null mutants display early embryonic lethality, we used a conditional knockout strategy to examine the role of LDB1 in early forebrain development using multiple Cre lines. Loss ofLdb1from E8.75 using Foxg1Cre caused a disruption of midline boundary structures in the dorsal telencephalon. While this Cre line gave the expected pattern of recombination of the floxedLdb1locus, unexpectedly, standard Cre lines that act from embryonic day (E)10.5 (Emx1Cre) and E11.5 (NesCre) did not show efficient or complete recombination in the dorsal telencephalon by E12.5. Intriguingly, this effect was specific to theLdb1floxed allele, since three other lines including floxed Ai9 and mTmG reporters, and a floxedLhx2line, each displayed the expected spatial patterns of recombination. Furthermore, the incomplete recombination of the floxedLdb1locus using NesCre was limited to the dorsal telencephalon, while the ventral telencephalon and the diencephalon displayed the expected loss ofLdb1. This permitted us to examine the requirement for LDB1 in the development of the thalamus in a context wherein the cortex continued to expressLdb1. We report that the somatosensory VB nucleus is profoundly shrunken upon loss of LDB1. Our findings highlight the unusual nature of theLdb1locus in terms of recombination efficiency, and also report a novel role for LDB1 during the development of the thalamus.

During appendicular skeletal development, the bi-potential cartilage anlagen gives rise to transient cartilage, which is eventually replaced by bone, and articular cartilage which caps the ends of individual skeletal elements. While the molecular mechanism that regulates transient cartilage differentiation is relatively better understood, the mechanism of articular cartilage differentiation has only begun to be unraveled. Further, the molecules that coordinate articular and transient cartilage differentiation processes are very poorly understood. Here, we have characterized the regulatory roles of two transcription factors, NFIA and GATA3 in articular cartilage differentiation, maintenance and the coordinated differentiation of articular and transient cartilage. Both NFIA and GATA3 block hypertrophic differentiation. Our results suggest that NFIA is not sufficient but necessary for articular cartilage differentiation. On the other hand, while ectopic activation of GATA3 promotes articular cartilage differentiation, inhibition of GATA3 activity promotes transient cartilage differentiation at the expense of articular cartilage. Finally, we propose a novel transcriptional circuitry involved in embryonic articular cartilage differentiation, maintenance and its cross-talk with transient cartilage differentiation program.