Dlx1/2 and Otp coordinate the production of hypothalamic GHRH- and AgRP-neurons

Bora Lee; Janghyun Kim; Taekyeong An; Sangsoo Kim; Esha M. Patel; Jacob Raber; Soo Kyung Lee; Seunghee Lee; Jae W. Lee

doi:10.1038/s41467-018-04377-4

Dlx1/2 and Otp coordinate the production of hypothalamic GHRH- and AgRP-neurons

Bora Lee, Janghyun Kim, Taekyeong An, Sangsoo Kim, Esha M. Patel, Jacob Raber, Soo Kyung Lee, Seunghee Lee, Jae W. Lee

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Despite critical roles of the hypothalamic arcuate neurons in controlling the growth and energy homeostasis, the gene regulatory network directing their development remains unclear. Here we report that the transcription factors Dlx1/2 and Otp coordinate the balanced generation of the two functionally related neurons in the hypothalamic arcuate nucleus, GHRH-neurons promoting the growth and AgRP-neurons controlling the feeding and energy expenditure. Dlx1/2-deficient mice show a loss-of-GHRH-neurons and an increase of AgRP-neurons, and consistently develop dwarfism and consume less energy. These results indicate that Dlx1/2 are crucial for specifying the GHRH-neuronal identity and, simultaneously, for suppressing AgRP-neuronal fate. We further show that Otp is required for the generation of AgRP-neurons and that Dlx1/2 repress the expression of Otp by directly binding the Otp gene. Together, our study demonstrates that the identity of GHRH- and AgRP-neurons is synchronously specified and segregated by the Dlx1/2-Otp gene regulatory axis.

Original language	English (US)
Article number	2026
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04377-4
State	Published - Dec 1 2018

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-018-04377-4

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title = "Dlx1/2 and Otp coordinate the production of hypothalamic GHRH- and AgRP-neurons",

abstract = "Despite critical roles of the hypothalamic arcuate neurons in controlling the growth and energy homeostasis, the gene regulatory network directing their development remains unclear. Here we report that the transcription factors Dlx1/2 and Otp coordinate the balanced generation of the two functionally related neurons in the hypothalamic arcuate nucleus, GHRH-neurons promoting the growth and AgRP-neurons controlling the feeding and energy expenditure. Dlx1/2-deficient mice show a loss-of-GHRH-neurons and an increase of AgRP-neurons, and consistently develop dwarfism and consume less energy. These results indicate that Dlx1/2 are crucial for specifying the GHRH-neuronal identity and, simultaneously, for suppressing AgRP-neuronal fate. We further show that Otp is required for the generation of AgRP-neurons and that Dlx1/2 repress the expression of Otp by directly binding the Otp gene. Together, our study demonstrates that the identity of GHRH- and AgRP-neurons is synchronously specified and segregated by the Dlx1/2-Otp gene regulatory axis.",

author = "Bora Lee and Janghyun Kim and Taekyeong An and Sangsoo Kim and Patel, {Esha M.} and Jacob Raber and Lee, {Soo Kyung} and Seunghee Lee and Lee, {Jae W.}",

note = "Funding Information: We thank Dr. Daniel Marks for critically reading this manuscript. We thank Dr. Shaun Morrison's lab for helping us with the body temperature measurement. We also thank Drs. Dario Acampora and Dr. Magdalena Petryniak for providing Otp+/− and Dlx1/2f/f mice, respectively. This research was supported by grants from the NIH/NINDS (R01 NS054941 to S.-K.L.) and NIH/NIDDK (R01 DK064678 to J.W.L.; R01 DK103661, to S.-K.L. and J.W.L.), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (HI17C0447 to S.L.), and National Research Foundation of Korea (NRF-2012M3A9D1054705 to S.K.). This work was partially supported by the development account of Dr. Raber.",

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doi = "10.1038/s41467-018-04377-4",

language = "English (US)",

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T1 - Dlx1/2 and Otp coordinate the production of hypothalamic GHRH- and AgRP-neurons

AU - Lee, Bora

AU - Kim, Janghyun

AU - An, Taekyeong

AU - Kim, Sangsoo

AU - Patel, Esha M.

AU - Raber, Jacob

AU - Lee, Soo Kyung

AU - Lee, Seunghee

AU - Lee, Jae W.

N1 - Funding Information: We thank Dr. Daniel Marks for critically reading this manuscript. We thank Dr. Shaun Morrison's lab for helping us with the body temperature measurement. We also thank Drs. Dario Acampora and Dr. Magdalena Petryniak for providing Otp+/− and Dlx1/2f/f mice, respectively. This research was supported by grants from the NIH/NINDS (R01 NS054941 to S.-K.L.) and NIH/NIDDK (R01 DK064678 to J.W.L.; R01 DK103661, to S.-K.L. and J.W.L.), the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (HI17C0447 to S.L.), and National Research Foundation of Korea (NRF-2012M3A9D1054705 to S.K.). This work was partially supported by the development account of Dr. Raber.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Despite critical roles of the hypothalamic arcuate neurons in controlling the growth and energy homeostasis, the gene regulatory network directing their development remains unclear. Here we report that the transcription factors Dlx1/2 and Otp coordinate the balanced generation of the two functionally related neurons in the hypothalamic arcuate nucleus, GHRH-neurons promoting the growth and AgRP-neurons controlling the feeding and energy expenditure. Dlx1/2-deficient mice show a loss-of-GHRH-neurons and an increase of AgRP-neurons, and consistently develop dwarfism and consume less energy. These results indicate that Dlx1/2 are crucial for specifying the GHRH-neuronal identity and, simultaneously, for suppressing AgRP-neuronal fate. We further show that Otp is required for the generation of AgRP-neurons and that Dlx1/2 repress the expression of Otp by directly binding the Otp gene. Together, our study demonstrates that the identity of GHRH- and AgRP-neurons is synchronously specified and segregated by the Dlx1/2-Otp gene regulatory axis.

AB - Despite critical roles of the hypothalamic arcuate neurons in controlling the growth and energy homeostasis, the gene regulatory network directing their development remains unclear. Here we report that the transcription factors Dlx1/2 and Otp coordinate the balanced generation of the two functionally related neurons in the hypothalamic arcuate nucleus, GHRH-neurons promoting the growth and AgRP-neurons controlling the feeding and energy expenditure. Dlx1/2-deficient mice show a loss-of-GHRH-neurons and an increase of AgRP-neurons, and consistently develop dwarfism and consume less energy. These results indicate that Dlx1/2 are crucial for specifying the GHRH-neuronal identity and, simultaneously, for suppressing AgRP-neuronal fate. We further show that Otp is required for the generation of AgRP-neurons and that Dlx1/2 repress the expression of Otp by directly binding the Otp gene. Together, our study demonstrates that the identity of GHRH- and AgRP-neurons is synchronously specified and segregated by the Dlx1/2-Otp gene regulatory axis.

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U2 - 10.1038/s41467-018-04377-4

DO - 10.1038/s41467-018-04377-4

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AN - SCOPUS:85047529530

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 2026

ER -

Dlx1/2 and Otp coordinate the production of hypothalamic GHRH- and AgRP-neurons

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