Manipulation of Signal Gradient and Transcription Factors Recapitulates : Multiple Hypothalamic Identities
Yamamoto, Maho ; Ong, Agnes Lee Chen LU
; Shinozuka, Takuma
; Shirai, Manabu
and Sasai, Noriaki
(2023)
In Stem Cells
41(5).
p.453-467
- Abstract
During development, the hypothalamus emerges from the ventral diencephalon and is regionalized into several distinct functional domains. Each domain is characterized 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... (More)
During development, the hypothalamus emerges from the ventral diencephalon and is regionalized into several distinct functional domains. Each domain is characterized 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 signaling and its downstream transcription network are required for hypothalamic regionalization and establishment.
(Less)
- author
- Yamamoto, Maho
; Ong, Agnes Lee Chen
LU
; Shinozuka, Takuma
; Shirai, Manabu
and Sasai, Noriaki
- publishing date
- 2023-05
- type
- Contribution to journal
- publication status
- published
- keywords
- chick embryo, CRISPR/Cas9, gene reporter mouse, hypothalamus, sonic hedgehog, transcription network
- in
- Stem Cells
- volume
- 41
- issue
- 5
- pages
- 453 - 467
- publisher
- Oxford University Press
- external identifiers
-
- scopus:85159737704
- pmid:36866456
- ISSN
- 1066-5099
- DOI
- 10.1093/stmcls/sxad018
- language
- English
- LU publication?
- no
- additional info
- Publisher Copyright: © 2023 The Author(s). Published by Oxford University Press. All rights reserved.
- id
- 60f18c62-5f9b-40c1-9171-e42a82032a9a
- date added to LUP
- 2026-01-23 23:19:33
- date last changed
- 2026-01-27 03:55:20
@article{60f18c62-5f9b-40c1-9171-e42a82032a9a,
abstract = {{<p>During development, the hypothalamus emerges from the ventral diencephalon and is regionalized into several distinct functional domains. Each domain is characterized 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 signaling and its downstream transcription network are required for hypothalamic regionalization and establishment.</p>}},
author = {{Yamamoto, Maho and Ong, Agnes Lee Chen and Shinozuka, Takuma and Shirai, Manabu and Sasai, Noriaki}},
issn = {{1066-5099}},
keywords = {{chick embryo; CRISPR/Cas9; gene reporter mouse; hypothalamus; sonic hedgehog; transcription network}},
language = {{eng}},
number = {{5}},
pages = {{453--467}},
publisher = {{Oxford University Press}},
series = {{Stem Cells}},
title = {{Manipulation of Signal Gradient and Transcription Factors Recapitulates : Multiple Hypothalamic Identities}},
url = {{http://dx.doi.org/10.1093/stmcls/sxad018}},
doi = {{10.1093/stmcls/sxad018}},
volume = {{41}},
year = {{2023}},
}