Zmiz1 is a novel regulator of lymphatic endothelial cell gene expression and function

C, Rajan K; Patel, Nehal; Shenoy, Achut; Scallan, Joshua P.; Chiang, Mark Y.; Galazo, María J.; Meadows, Stryder M.

doi:10.1101/2023.07.22.550165

Cited by 2 publications

(1 citation statement)

References 63 publications

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“…VEGF is a known regulator of EGR3 and NR4A2 expression in endothelial cells ( 53 , 58 , 79 ). Human LECs up-regulate EGR3 and NR4A2 expression following VEGF stimulation ( 80 , 81 ), and a recent report on the transcriptional coactivator Zmiz1 suggests that Egr3 is also involved in lymphatic valve formation ( 82 ).…”

Section: Discussionmentioning

confidence: 99%

egr3 is a mechanosensitive transcription factor gene required for cardiac valve morphogenesis

da Silva,

Gunawan,

Boezio

et al. 2024

Sci. Adv.

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Biomechanical forces, and their molecular transducers, including key mechanosensitive transcription factor genes, such as KLF2 , are required for cardiac valve morphogenesis. However, klf2 mutants fail to completely recapitulate the valveless phenotype observed under no-flow conditions. Here, we identify the transcription factor EGR3 as a conserved biomechanical force transducer critical for cardiac valve formation. We first show that egr3 null zebrafish display a complete and highly penetrant loss of valve leaflets, leading to severe blood regurgitation. Using tissue-specific loss- and gain-of-function tools, we find that during cardiac valve formation, Egr3 functions cell-autonomously in endothelial cells, and identify one of its effectors, the nuclear receptor Nr4a2b. We further find that mechanical forces up-regulate egr3 / EGR3 expression in the developing zebrafish heart and in porcine valvular endothelial cells, as well as during human aortic valve remodeling. Altogether, these findings reveal that EGR3 is necessary to transduce the biomechanical cues required for zebrafish cardiac valve morphogenesis, and potentially for pathological aortic valve remodeling in humans.

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Section: Discussionmentioning

confidence: 99%

egr3 is a mechanosensitive transcription factor gene required for cardiac valve morphogenesis

da Silva,

Gunawan,

Boezio

et al. 2024

Sci. Adv.

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Zmiz1 is a novel regulator of brain development associated with autism and intellectual disability

K. C.,

Tiemroth,

Thurmon

et al. 2024

Front. Psychiatry

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Neurodevelopmental disorders (NDDs) are a class of pathologies arising from perturbations in brain circuit formation and maturation with complex etiological triggers often classified as environmental and genetic. Neuropsychiatric conditions such as autism spectrum disorders (ASD), intellectual disability (ID), and attention deficit hyperactivity disorders (ADHD) are common NDDs characterized by their hereditary underpinnings and inherent heterogeneity. Genetic risk factors for NDDs are increasingly being identified in non-coding regions and proteins bound to them, including transcriptional regulators and chromatin remodelers. Importantly, de novo mutations are emerging as important contributors to NDDs and neuropsychiatric disorders. Recently, de novo mutations in transcriptional co-factor Zmiz1 or its regulatory regions have been identified in unrelated patients with syndromic ID and ASD. However, the role of Zmiz1 in brain development is unknown. Here, using publicly available databases and a Zmiz1 mutant mouse model, we reveal that Zmiz1 is highly expressed during embryonic brain development in mice and humans, and though broadly expressed across the brain, Zmiz1 is enriched in areas prominently impacted in ID and ASD such as cortex, hippocampus, and cerebellum. We investigated the relationship between Zmiz1 structure and pathogenicity of protein variants, the epigenetic marks associated with Zmiz1 regulation, and protein interactions and signaling pathways regulated by Zmiz1. Our analysis reveals that Zmiz1 regulates multiple developmental processes, including neurogenesis, neuron connectivity, and synaptic signaling. This work paves the way for future studies on the functions of Zmiz1 and highlights the importance of combining analysis of mouse models and human data.

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Zmiz1 is a novel regulator of lymphatic endothelial cell gene expression and function

Cited by 2 publications

References 63 publications

egr3 is a mechanosensitive transcription factor gene required for cardiac valve morphogenesis

egr3 is a mechanosensitive transcription factor gene required for cardiac valve morphogenesis

Zmiz1 is a novel regulator of brain development associated with autism and intellectual disability

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