Dysregulation of Grainyhead-like 3 expression causes widespread developmental defects

Deng, Z; Butt, T; Arhatari, BD; Darido, C; Auden, A; Swaroop, D; Partridge, DD; Haigh, K; Nguyen, T; Haigh, JJ; Carpinelli, MR; Jane, SM

Author(s): Deng, Z; Butt, T; Arhatari, BD; Darido, C; Auden, A; Swaroop, D; Partridge, DD; Haigh, K; Nguyen, T; Haigh, JJ; Carpinelli, MR; Jane, SM;
Details: Publication Year 2023-05,Volume 252,Issue #5,Page 647-667
Journal Title: Developmental Dynamics
Publication Type: Research article
Abstract: BACKGROUND: The gene encoding the transcription factor, Grainyhead-like 3 (Grhl3), plays critical roles in mammalian development and homeostasis. Grhl3-null embryos exhibit thoraco-lumbo-sacral spina bifida and soft-tissue syndactyly. Additional studies reveal that these embryos also exhibit an epidermal proliferation/differentiation imbalance. This manifests as skin barrier defects resulting in peri-natal lethality and defective wound repair. Despite these extensive analyses of Grhl3 loss-of-function models, the consequences of gain-of-function of this gene have been difficult to achieve. RESULTS: In this study, we generated a novel mouse model that expresses Grhl3 from a transgene integrated in the Rosa26 locus on an endogenous Grhl3-null background. Expression of the transgene rescues both the neurulation and skin barrier defects of the knockout mice, allowing survival into adulthood. Despite this, the mice are not normal, exhibiting a range of phenotypes attributable to dysregulated Grhl3 expression. In mice homozygous for the transgene, we observe a severe Shaker-Waltzer phenotype associated with hearing impairment. Micro-CT scanning of the inner ear revealed profound structural alterations underlying these phenotypes. In addition, these mice exhibit other developmental anomalies including hair loss, digit defects, and epidermal dysmorphogenesis. CONCLUSION: Taken together, these findings indicate that diverse developmental processes display low tolerance to dysregulation of Grhl3.
Publisher: Wiley
Keywords: Mice; Animals; *DNA-Binding Proteins/genetics; Transcription Factors/metabolism; *Spinal Dysraphism/genetics; Epidermis/metabolism; Mice, Knockout; Mammals/metabolism; Grhl3 overexpression; Shaker-Waltzer phenotype; inner ear malformation; neural tube defects; skin barrier defects
Department(s): Laboratory Research
PubMed ID: 36606449
Publisher's Version: https://doi.org/10.1002/dvdy.565
Open Access at Publisher's Site: https://doi.org/10.1002/dvdy.565
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-08-15 07:31:23

Last Modified: 2023-08-15 07:32:14