Highlights d Hypothalamic-pituitary functional units can be generated from 3D-cultured human iPS cells d Maturation of induced pituitary through simultaneous culture with hypothalamic neurons d ACTH secretion ability of induced pituitary is comparable with adult mice d Induced pituitary cells respond to low-glucose stimulation through the CRH-ACTH pathway SUMMARYThe pituitary is a major hormone center that secretes systemic hormones responding to hypothalamusderived-releasing hormones. Previously, we reported the independent pituitary induction and hypothalamic differentiation of human embryonic stem cells (ESCs).Here, a functional hypothalamic-pituitary unit is generated using human induced pluripotent stem (iPS) cells in vitro. The adrenocorticotropic hormone (ACTH) secretion capacity of the induced pituitary reached a comparable level to that of adult mouse pituitary because of the simultaneous maturation with hypothalamic neurons within the same aggregates. Corticotropin-releasing hormone (CRH) from the hypothalamic area regulates ACTH cells similarly to our hypothalamic-pituitary axis. Our induced hypothalamic-pituitary units respond to environmental hypoglycemic condition in vitro, which mimics a lifethreatening situation in vivo, through the CRH-ACTH pathway, and succeed in increasing ACTH secretion. Thus, we generated powerful hybrid organoids by recapitulating hypothalamic-pituitary development, showing autonomous maturation on the basis of interactions between developing tissues.

Arginine-vasopressin (AVP) neurons exist in the hypothalamus, a major region of the diencephalon, and play an essential role in water balance. Here, we established the differentiation method for AVP-secreting neurons from human embryonic stem cells (hESCs) by recapitulating in vitro the in vivo embryonic developmental processes of AVP neurons. At first, the differentiation efficiency was improved. That was achieved through the optimization of the culture condition for obtaining dorsal hypothalamic progenitors. Secondly, the induced AVP neurons were identified by immunohistochemistry and these neurons secreted AVP after potassium chloride stimulation. Additionally, other hypothalamic neuropeptides were also detected, such as oxytocin, corticotropin-releasing hormone, thyrotropin-releasing hormone, pro-opiomelanocortin, agouti-related peptide, orexin, and melanin-concentrating hormone. This is the first report describing the generation of secretory AVP neurons derived from hESCs. This method will be applicable to research using disease models and, potentially, for regenerative medicine of the hypothalamus.

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Short and Convergent Synthesis of Asterriquinone Bl and Demethylasterriquinone Bl Sir: Asterriquinone Bl (1) and its de-(9-methyl analog, demethylasterriquinone Bl (2), which are members of a group of bis-indolyl benzoquinones, were isolated from strains of Aspergillus terreus^and Pseudomassaria sp.,2) respectively. Especially, the latter product 2 has been reported by Merck group to be the novel insulin receptor activator, that mimics the function of insulin, and therefore, is of potential therapeutic interest for the treatment of diabetes.2) The total synthesis of the natural products 1 and 2 has been also accomplished by Merck group using elegant strategies with the rearrangement of pyrandione.3) Wedescribe herein a short and convergent synthesis of asterriquinone B l (1) and demethylasterriquinone B l (2). The construction of 1 and 2 entailed the synthesis of three building blocks, the substituted indols 3 and 5 and the dibromoquinone 4, as depicted in Fig. 1. Compounds 3 and 4 were prepared from 2-iodoaniline (6) and 2,5-dimethoxy-l,4-quinone (7) by the reported

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