In vertebrates, two homologous heterotetrameric AP1 complexes regulate the intracellular protein sorting via vesicles. AP-1 complexes are ubiquitously expressed and are composed of four different subunits: gamma, beta 1, mu 1 and sigma 1. Two different complexes are present in eukaryotic cells, AP1G1 (contains gamma 1 subunit) and AP1G2 (contains gamma 2 subunit); both are indispensable for development. One additional tissue-specific isoform exists for mu 1A, the polarized epithelial cells specific to mu 1B; two additional tissue-specific isoforms exist for sigma 1A: sigma 1B and sigma 1C. Both AP1 complexes fulfil specific functions at the trans-Golgi network and endosomes. The use of different animal models demonstrated their crucial role in the development of multicellular organisms and the specification of neuronal and epithelial cells. Ap1g1 (gamma 1) knockout mice cease development at the blastocyst stage, while Ap1m1 (mu 1A) knockouts cease during mid-organogenesis. A growing number of human diseases have been associated with mutations in genes encoding for the subunits of adaptor protein complexes. Recently, a new class of neurocutaneous and neurometabolic disorders affecting intracellular vesicular traffic have been referred to as adaptinopathies. To better understand the functional role of AP1G1 in adaptinopathies, we generated a zebrafish ap1g1 knockout using CRISPR/Cas9 genome editing. Zebrafish ap1g1 knockout embryos cease their development at the blastula stage. Interestingly, heterozygous females and males have reduced fertility and showed morphological alterations in the brain, gonads and intestinal epithelium. An analysis of mRNA profiles of different marker proteins and altered tissue morphologies revealed dysregulated cadherin-mediated cell adhesion. These data demonstrate that the zebrafish model organism enables us to study the molecular details of adaptinopathies and thus also develop treatment strategies.

Deficiency of AP1 Complex Ap1g1 in Zebrafish Model Led to Perturbation of Neurodevelopment, Female and Male Fertility; New Insight to Understand Adaptinopathies

Mignani L.;Varinelli M.;Massardi E.;Mitola S.;Monti E.;Finazzi D.;Borsani G.;Zizioli D.
2023-01-01

Abstract

In vertebrates, two homologous heterotetrameric AP1 complexes regulate the intracellular protein sorting via vesicles. AP-1 complexes are ubiquitously expressed and are composed of four different subunits: gamma, beta 1, mu 1 and sigma 1. Two different complexes are present in eukaryotic cells, AP1G1 (contains gamma 1 subunit) and AP1G2 (contains gamma 2 subunit); both are indispensable for development. One additional tissue-specific isoform exists for mu 1A, the polarized epithelial cells specific to mu 1B; two additional tissue-specific isoforms exist for sigma 1A: sigma 1B and sigma 1C. Both AP1 complexes fulfil specific functions at the trans-Golgi network and endosomes. The use of different animal models demonstrated their crucial role in the development of multicellular organisms and the specification of neuronal and epithelial cells. Ap1g1 (gamma 1) knockout mice cease development at the blastocyst stage, while Ap1m1 (mu 1A) knockouts cease during mid-organogenesis. A growing number of human diseases have been associated with mutations in genes encoding for the subunits of adaptor protein complexes. Recently, a new class of neurocutaneous and neurometabolic disorders affecting intracellular vesicular traffic have been referred to as adaptinopathies. To better understand the functional role of AP1G1 in adaptinopathies, we generated a zebrafish ap1g1 knockout using CRISPR/Cas9 genome editing. Zebrafish ap1g1 knockout embryos cease their development at the blastula stage. Interestingly, heterozygous females and males have reduced fertility and showed morphological alterations in the brain, gonads and intestinal epithelium. An analysis of mRNA profiles of different marker proteins and altered tissue morphologies revealed dysregulated cadherin-mediated cell adhesion. These data demonstrate that the zebrafish model organism enables us to study the molecular details of adaptinopathies and thus also develop treatment strategies.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11379/576327
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