During development, the hypothalamus emerges from the ventral diencephalon and is regionalised into several distinct functional domains. Each domain is characterised by a different combination of transcription factors, including Nkx2.1, Nkx2.2, Pax6, and Rx, which are expressed in the presumptive hypothalamus and its surrounding regions, and play critical roles in defining each area. Here, we recapitulated the molecular networks formed by the gradient of Sonic Hedgehog (Shh) and the aforementioned transcription factors. Using combinatorial experimental systems of directed neural differentiation of mouse embryonic stem (ES) cells, as well as a reporter mouse line and gene overexpression in chick embryos, we deciphered the regulation of transcription factors by different Shh signal intensities. We then used CRISPR/Cas9 mutagenesis to demonstrate the mutual repression between Nkx2.1 and Nkx2.2 in a cell-autonomous manner; however, they induce each other in a non-cell-autonomous manner. Moreover, Rx resides upstream of all these transcription factors and determines the location of the hypothalamic region. Our findings suggest that Shh signalling and its downstream transcription network are required for hypothalamic regionalisation and establishment.
The neural tube comprises several different types of progenitors and postmitotic neurons that coordinately act with each other to play integrated functions. Its development consists of two phases: proliferation of progenitor cells and differentiation into postmitotic neurons. How progenitor cells differentiate into each corresponding neuron is an important question for understanding the mechanisms of neuronal development. Here we introduce one of the Sox transcription factors, Sox14, which plays an essential role in the promotion of neuronal differentiation. Sox14 belongs to the SoxB subclass and its expression starts in the progenitor regions before neuronal differentiation is initiated at the trunk level of the neural tube. After neuronal differentiation is initiated, Sox14 expression gradually becomes confined to the V2a region of the neural tube, where Chx10 is co-expressed. Overexpression of Sox14 restricts progenitor cell proliferation. Conversely, the blockade of Sox14 expression by the RNAi strategy inhibits V2a neuron differentiation and causes expansion of the progenitor domain. We further found that Sox14 acted as a transcriptional activator. Taken together, Sox14 acts as a modulator of cell proliferation and an initiator protein for neuronal differentiation in the intermediate region of the neural tube.
Background: Subarachnoid hemorrhage due to rupture of an intracranial aneurysm (IA) has quite a poor prognosis once after the onset despite of the modern technical advancement. The development of a novel therapeutic modality to prevent rupture or a diagnostic method to stratify dangerous lesions from many stable ones is thus mandatory for social health. To this end, mechanisms underlying rupture of lesions should be clarified. Methods: We and others have developed the rat model in which induced IAs spontaneously rupture resulting in subarachnoid hemorrhage. To clarify molecular cascades regulating rupture, we obtained gene expression profile data from rupture-prone lesions and revealed the enrichment of neutrophil-related terms in rupture-prone lesions by Gene Ontology analysis. Next, to validate a role of neutrophils in rupture of lesions, G-CSF was administered to a rat model. Results: As a result, G-CSF treatment not only increased number of neutrophils infiltrating in lesions but also significantly facilitated rupture of the lesions without increase the incidence. To clarify mechanisms how neutrophils facilitate rupture of IAs, we used HL-60 cell line and found that inflammatory stimuli enhanced the collagenolytic activity of MMP9. Immunohistochemical study using IA lesions from a rat model identified neutrophils as a major type of cells producing MMP9 around a site of rupture and consistently the collagenolytic activity of MMP9 was detected in ruptured lesions. Conclusions: These results combined together suggest the crucial role of neutrophil to rupture of IAs and also propose the potential of this type of cells as a candidate of therapeutic or diagnostic targets.
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