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The embryonic patterning gene Dbx1 governs the survival of the auditory midbrain via Tcf7l2-Ap2δ transcriptional cascade

Cell Death & Differentiation volume 30, pages 1563–1574 (2023)Cite this article

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Abstract

At the top of the midbrain is the inferior colliculus (IC), which functions as the major hub for processing auditory information. Despite the functional significance of neurons in the IC, our understanding of their formation is limited. In this study, we identify the embryonic patterning gene Dbx1 as a key molecular player that governs genetic programs for IC survival. We find that Dbx1 plays a critical role in preventing apoptotic cell death in postnatal IC by transcriptionally repressing c-Jun and pro-apoptotic BH3 only factors. Furthermore, by employing combined approaches, we uncover that Tcf7l2 functions downstream of Dbx1. Loss of Tcf7l2 function causes IC phenotypes with striking similarity to those of Dbx1 mutant mice, which include defective embryonic maturation and postnatal deletion of the IC. Finally, we demonstrate that the Dbx1-Tcf7l2 cascade functions upstream of Ap-2δ, which is essential for IC development and survival. Together, these results unravel a novel molecular mechanism for IC maintenance, which is indispensable for normal brain development.

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Fig. 1: Differential expression profiling identifies Dbx1 target genes in the IC.
Fig. 2: Loss of Dbx1 leads to increased levels of c-Jun and BH3 only factors, and to cell death in the IC.
Fig. 3: Absence of the inferior colliculus in Dbx1cko mutant mice.
Fig. 4: Tcf7l2 acts downstream of Dbx1 to orchestrate a genetic program of morphological maturation in the developing IC.
Fig. 5: Tcf7l2 inactivation leads to apoptosis and lack of the inferior colliculus.
Fig. 6: Ap-2δ is co-regulated by Dbx1 and Tcf7l2 in the IC.
Fig. 7: Restored expression of Tcf7l2 and/or Ap-2δ attenuates apoptosis in Dbx1-deficient IC cells.

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Data availability

RNA-seq raw FASTQ files of wildtype and Dbx1 mutants have been deposited into the NCBI Sequence Read Archive under bioproject ID PRJNA793387. RNA-seq raw FASTQ files of wildtype and Tcf7l2 mutants have been deposited into the NCBI Sequence Read Archive under bioproject ID PRJNA801436.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea Ministry of Science and ICT (No. 2019R1F1A1042941 and No. 2022R1F1A1064555).

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Authors and Affiliations

  1. Department of Genetics and Biotechnology, College of Life Sciences, Graduate School of Biotechnology, Kyung Hee University, Yongin, Gyeonggi, Republic of Korea

    Hong-Nhung Tran, Quy-Hoai Nguyen, Ji-eun Jeong, Duc-Linh Loi, Jaeseung Yoon, Kwanghee Baek & Yongsu Jeong

  2. Department of Oriental Medicine Biotechnology, Kyung Hee University, Yongin, Gyeonggi, Republic of Korea

    Youn Hee Nam & Tong Ho Kang

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Conceived project: YJ. Designed experiments: HT, YJ. Performed experiments: HT, QN, JJ, DL. Analyzed data: HT, QN, JJ, DL, YJ. Provided reagents: YN, TK, JY, KB, Wrote paper: YJ. Reviewed and revised the paper: HT, QN, JJ, DL, YJ.

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Tran, HN., Nguyen, QH., Jeong, Je. et al. The embryonic patterning gene Dbx1 governs the survival of the auditory midbrain via Tcf7l2-Ap2δ transcriptional cascade. Cell Death Differ 30, 1563–1574 (2023). https://doi.org/10.1038/s41418-023-01165-6

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