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Fig. 6. A biophysical model of the mechanisms controlling tail regeneration.
(A-F) Schematics of the physiological events occurring in tails under
different conditions. The intact tail (A,A') is generally
hyperpolarized, with a distributed pattern of depolarized cells. The
regenerating tail exhibits a bud that is first depolarized (B) but is then
repolarized by the normal expression of the V-ATPase or induced expression of
the PMA H+-pump (B'); by 24 hpa, a depolarized cell group has
appeared in the center of the trunk just anterior to the bud (the `shoulder
region'). (C) V-ATPase-inhibited, or PTX-treated, tails are fully depolarized
and are not able to repolarize the bud by 24 hpa (C'). (D,D')
Refractory tails are likewise unable to repolarize the bud and do not possess
a depolarized cell group in the shoulder region. (E) Thus, the tail possesses
two separate biophysical components: a transepithelial potential normally
driven by proton-extruder expression at the edge [likely to result in an
electric field (curved lines) that may guide axons into the bud], and a
population of cells in the shoulder region that becomes depolarized in tails
capable of regenerating. (F) The significance of the shoulder region is
unknown, but it may be a region of highly active morphogenesis, as evidenced
by the disorganization of the mature melanocytes in this region. (G) A
step-wise model of tail regeneration consisting of physiological, gene
expression and morphogenetic modules. Amputation triggers a cassette of ion
transporter expression in existing cells, with V-ATPase expressed as early as
6 hpa and inducing KCNK1 (12-24 hpa). This results in a particular pattern of
relative hyper- and depolarization in the regeneration bud and shoulder cells,
respectively (characterized at 24 hpa in
Fig. 3). A key parameter here
is the physiological condition of bud cells (membrane voltage); when
hyperpolarized by the activity of a H+ pump, whether naturally or
through judicious misexpression of specific transporters, this leads to
depolarization in a rostral cell group (24 hpa), an upregulation of mitosis
(48 hpa), and subsequent axonal outgrowth (48-72 hpa), ultimately resulting in
the regeneration of the complete tail. Refractory-stage larvae cannot
regenerate owing to a failure to repolarize the bud and depolarize shoulder
region cells. Ectopically-induced H+ flux can rescue upstream steps
and initiate the program of regeneration, thus representing a tractable
initiation point for therapeutic approaches.
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