Dataset Information

An essential role for the nuclear protein Akirin2 in mouse limb interdigital tissue regression.

ABSTRACT: The regulation of interdigital tissue regression requires the interplay of multiple spatiotemporally-controlled morphogen gradients to ensure proper limb formation and release of individual digits. Disruption to this process can lead to a number of limb abnormalities, including syndactyly. Akirins are highly conserved nuclear proteins that are known to interact with chromatin remodelling machinery at gene enhancers. In mammals, the analogue Akirin2 is essential for embryonic development and critical for a wide variety of roles in immune function, meiosis, myogenesis and brain development. Here we report a critical role for Akirin2 in the regulation of interdigital tissue regression in the mouse limb. Knockout of Akirin2 in limb epithelium leads to a loss of interdigital cell death and an increase in cell proliferation, resulting in retention of the interdigital web and soft-tissue syndactyly. This is associated with perdurance of Fgf8 expression in the ectoderm overlying the interdigital space. Our study supports a mechanism whereby Akirin2 is required for the downregulation of Fgf8 from the apical ectodermal ridge (AER) during limb development, and implies its requirement in signalling between interdigital mesenchymal cells and the AER.

SUBMITTER: Bosch PJ

PROVIDER: S-EPMC6095873 | biostudies-other | 2018 Aug

REPOSITORIES: biostudies-other

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An essential role for the nuclear protein Akirin2 in mouse limb interdigital tissue regression.

Bosch Peter J PJ Fuller Leah C LC Weiner Joshua A JA

Scientific reports 20180816 1

The regulation of interdigital tissue regression requires the interplay of multiple spatiotemporally-controlled morphogen gradients to ensure proper limb formation and release of individual digits. Disruption to this process can lead to a number of limb abnormalities, including syndactyly. Akirins are highly conserved nuclear proteins that are known to interact with chromatin remodelling machinery at gene enhancers. In mammals, the analogue Akirin2 is essential for embryonic development and crit ...[more]

PMID: 30116001

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Project description:The primordium of the limb contains a number of progenitors far superior to those necessary to form the skeletal components of this appendage. During the course of development, precursors that do not follow the skeletogenic program are removed by cell senescence and apoptosis. The formation of the digits provides the most representative example of embryonic remodeling via cell degeneration. In the hand/foot regions of the embryonic vertebrate limb (autopod), the interdigital tissue and the zones of interphalangeal joint formation undergo massive degeneration that accounts for jointed and free digit morphology. Developmental senescence and caspase-dependent apoptosis are considered responsible for these remodeling processes. Our study uncovers a new upstream level of regulation of remodeling by the epigenetic regulators Uhrf1 and Uhrf2 genes. These genes are spatially and temporally expressed in the pre-apoptotic regions. UHRF1 and UHRF2 showed a nuclear localization associated with foci of methylated cytosine. Interestingly, nuclear labeling increased in cells progressing through the stages of degeneration prior to TUNEL positivity. Functional analysis in cultured limb skeletal progenitors via the overexpression of either UHRF1 or UHRF2 inhibited chondrogenesis and induced cell senescence and apoptosis accompanied with changes in global and regional DNA methylation. Uhrfs modulated canonical cell differentiation factors, such as Sox9 and Scleraxis, promoted apoptosis via up-regulation of Bak1, and induced cell senescence, by arresting progenitors at the S phase and upregulating the expression of p21. Expression of Uhrf genes in vivo was positively modulated by FGF signaling. In the micromass culture assay Uhrf1 was down-regulated as the progenitors lost stemness and differentiated into cartilage. Together, our findings emphasize the importance of tuning the balance between cell differentiation and cell stemness as a central step in the initiation of the so-called "embryonic programmed cell death" and suggest that the structural organization of the chromatin, via epigenetic modifications, may be a precocious and critical factor in these regulatory events.

Dataset Information

An essential role for the nuclear protein Akirin2 in mouse limb interdigital tissue regression.

Publications

An essential role for the nuclear protein Akirin2 in mouse limb interdigital tissue regression.

Similar Datasets

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