Reconstitution of human adrenocortical specification and steroidogenesis using induced pluripotent stem cells

Sakata, Yuka; Cheng, Keren; Mayama, Michinori; Seita, Yasunari; Detlefsen, Andrea J.; Mesaros, Clementina; Penning, T.M.; Shishikura, Kyosuke; Yang, Wenli; Auchus, Richard J.; Strauss, Jerome F.; Sasaki, Kotaro

doi:10.1016/j.devcel.2022.10.010

Cited by 10 publications

(11 citation statements)

References 45 publications

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“…The identification of upstream factors and signaling pathways finely tuning the differential expression of SF-1 in the different cell layers of the human fetal adrenal gland is then of utmost importance for future studies. This may be made easier by the recent development of an in vitro system to produce human fetal adrenal cells from induced pluripotent stem cells (iPS) [ 114 ].…”

Section: Sf-1 Dosage-dependent Target Genes: Their Roles In Acc and I...mentioning

confidence: 99%

Steroidogenic Factor 1, a Goldilocks Transcription Factor from Adrenocortical Organogenesis to Malignancy

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Doghman

Ruggiero

et al. 2023

IJMS

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Steroidogenic factor-1 (SF-1, also termed Ad4BP; NR5A1 in the official nomenclature) is a nuclear receptor transcription factor that plays a crucial role in the regulation of adrenal and gonadal development, function and maintenance. In addition to its classical role in regulating the expression of P450 steroid hydroxylases and other steroidogenic genes, involvement in other key processes such as cell survival/proliferation and cytoskeleton dynamics have also been highlighted for SF-1. SF-1 has a restricted pattern of expression, being expressed along the hypothalamic-pituitary axis and in steroidogenic organs since the time of their establishment. Reduced SF-1 expression affects proper gonadal and adrenal organogenesis and function. On the other hand, SF-1 overexpression is found in adrenocortical carcinoma and represents a prognostic marker for patients’ survival. This review is focused on the current knowledge about SF-1 and the crucial importance of its dosage for adrenal gland development and function, from its involvement in adrenal cortex formation to tumorigenesis. Overall, data converge towards SF-1 being a key player in the complex network of transcriptional regulation within the adrenal gland in a dosage-dependent manner.

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Section: Sf-1 Dosage-dependent Target Genes: Their Roles In Acc and I...mentioning

confidence: 99%

Steroidogenic Factor 1, a Goldilocks Transcription Factor from Adrenocortical Organogenesis to Malignancy

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Doghman

Ruggiero

et al. 2023

IJMS

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“…Quantitative RT-PCR (qPCR) was performed as described previously 42,82 . Briefly, cell pellet were lysed for RNA isolation using RNeasy Micro Kit (Qiagen).…”

Section: Methods Detailsmentioning

confidence: 99%

Defining the cellular origin of seminoma by transcriptional and epigenetic mapping to the normal human germline

Cheng,

Seita,

Whelan

et al. 2024

Preprint

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Aberrant male germline development can lead to the formation of seminoma, a testicular germ cell tumor. Seminomas are biologically similar to primordial germ cells (PGCs) and many bear an isochromosome 12p [i(12p)] with two additional copies of the short arm of chromosome 12. By mapping seminoma transcriptomes and open chromatin landscape onto a normal human male germline trajectory, we find that seminoma resembles premigratory/migratory primordial germ cells, but exhibit enhanced germline and pluripotency programs, and upregulation of genes involved in apoptosis, angiogenesis, and MAPK/ERK pathways. Using pluripotent stem cell-derived PGCs from Pallister Killian syndrome patients mosaic for i(12p) to model seminoma, we identify gene dosage effects that may contribute to transformation. As murine seminoma models do not exist, our analyses provide critical insights into genetic, cellular and signaling programs driving seminoma transformation, and the newly developed in vitro platform permits evaluation of additional signals required for seminoma tumorigenesis.

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“…MC1-DTA-pA cassette synthesized by Gene Universal (Newark, DE) was inserted downstream of the right homology arm using Kpnl restriction sites (designated as YS42). The p2A-EGFP fragment with the PGK-puro cassette flanked by the loxP site was also PCR-amplified using the donor vector previously used to generate WT1-p2A-EGFP knock-in hiPSCs [ 31 ], and inserted in-frame at the 3’-end of the TFAP2C coding region obtained from YS42 through inverse PCR. TALEN’s RVD sequences were as follows: TFAP2C-left (5-prime), NN NN NI NN NI NI NI HD NI HD NI NN NN NI NI NI NG; TFAP2C-right (3-prime), NI HD NG HD NG HD HD NG NI NI HD HD NG NG NG HD NG.…”

Section: Methodsmentioning

confidence: 99%

CRISPR loss of function screening to identify genes involved in human primordial germ cell-like cell development

Hwang,

Seita,

Blanco

et al. 2023

PLoS Genet

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Despite our increasing knowledge of molecular mechanisms guiding various aspects of human reproduction, those underlying human primordial germ cell (PGC) development remain largely unknown. Here, we conducted custom CRISPR screening in an in vitro system of human PGC-like cells (hPGCLCs) to identify genes required for acquisition and maintenance of PGC fate. Amongst our candidates, we identified TCL1A, an AKT coactivator. Functional assessment in our in vitro hPGCLCs system revealed that TCL1A played a critical role in later stages of hPGCLC development. Moreover, we found that TCL1A loss reduced AKT-mTOR signaling, downregulated expression of genes related to translational control, and subsequently led to a reduction in global protein synthesis and proliferation. Together, our study highlights the utility of CRISPR screening for human in vitro-derived germ cells and identifies novel translational regulators critical for hPGCLC development.

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Reconstitution of human adrenocortical specification and steroidogenesis using induced pluripotent stem cells

Cited by 10 publications

References 45 publications

Steroidogenic Factor 1, a Goldilocks Transcription Factor from Adrenocortical Organogenesis to Malignancy

Steroidogenic Factor 1, a Goldilocks Transcription Factor from Adrenocortical Organogenesis to Malignancy

Defining the cellular origin of seminoma by transcriptional and epigenetic mapping to the normal human germline

CRISPR loss of function screening to identify genes involved in human primordial germ cell-like cell development

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