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.
Highlights
Limb development is a complex process involving the action of specialised signalling regions that coordinate both spatially and temporally to sculpt a limb of particular shape and structure suited to a given organism
At around embryonic day (E) 12.5 in mice, BMP2 and BMP4 released from the interdigital mesenchyme underlying the limb ectoderm activate BMP receptor/Smad signalling in the apical ectodermal ridge (AER), a pseudostratified epithelium that rims the dorsal-ventral border of the distal limb bud[21,22]
Akirin[2] is expressed throughout the developing limb bud, in both ectoderm and mesoderm, and loss of Akirin[2] from the ectoderm leads to soft-tissue syndactyly. This is due to reduced programmed cell death (PCD) and enduring cell proliferation in the relevant digits, and continued Fgf[8] expression in these digits beyond its normal physiological timeframe
Summary
Limb development is a complex process involving the action of specialised signalling regions that coordinate both spatially and temporally to sculpt a limb of particular shape and structure suited to a given organism. Loss of Akirin[2] in the limb ectoderm (using Emx1-Cre) results in a persistent soft-tissue syndactyly due to a lack of PCD and continued cell proliferation in interdigital tissues.
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