Enucleation is the culmination of terminal erythroid differentiation. It results in the release of 2 million new enucleate reticulocytes into your circulation and mine each second. In this issue of Blood, Ubukawa and colleagues shed new light on the mechanism, showing that non-muscle myosin IIb is intimately involved.1 

Photomicrographs illustrating the different steps during the enucleation process. The nucleus is first displaced to one side of the erythroblast (left panel). A contractile actin ring is then formed to begin to pinch off the nascent reticulocyte from the nucleus (middle panel). Subsequent redistribution of membrane between the 2 lobes of the dividing cell by vesicle shuttling further restricts the area of contact between the 2 emerging cells (right panel). Images courtesy of Dr Marcel Bessis.

Photomicrographs illustrating the different steps during the enucleation process. The nucleus is first displaced to one side of the erythroblast (left panel). A contractile actin ring is then formed to begin to pinch off the nascent reticulocyte from the nucleus (middle panel). Subsequent redistribution of membrane between the 2 lobes of the dividing cell by vesicle shuttling further restricts the area of contact between the 2 emerging cells (right panel). Images courtesy of Dr Marcel Bessis.

Mammalian red cells and their immediate precursors, reticulocytes, are, unlike their counterparts in some other vertebrates, devoid of nuclei as a result of an “asymmetric” cell division at the final step of terminal erythroid differentiation. Fission of the erythroblast generates the enucleate reticulocyte and a larger moiety in which an extruded nucleus is encased in a plasma membrane (pyrenocyte).2  There has over many years been keen interest in defining the molecular machinery responsible for enucleation and in the similarities and differences between this process and classic cytokinesis, which produces 2 identical daughter cells. By studying and comparing both processes, Ubukawa and colleagues offer new insights into the roles of various cytoskeletal proteins in the 2 cases.

Inhibition of non-muscle myosin II ATPase by blebbistatin blocked both cell division and enucleation, implying its participation in both processes and establishing a previously undefined role for myosin in enucleation. Nonmuscle myosin IIA and myosin IIb are both expressed during terminal erythroid differentiation and while both seem to be involved in cell division, a specific requirement for myosin IIb in enucleation was documented. Moreover, because inhibition of actin polymerization by cytochalasin D blocks both cell division and enucleation, an actomyosin-driven step in enucleation of erythroblasts during terminal erythroid differentiation may be inferred.

Enucleation is a multistep process (see figure) that requires displacement of the nucleus in the erythroblast to one side during the preparatory stage. This is followed by formation of a contractile actin ring, pinching off the nascent reticulocyte from the nucleus, and subsequent redistribution of membrane between the 2 lobes of the dividing cell by vesicle shuttling to restrict the area of contact between the 2 emerging cells.3  The coordinated execution of these diverse events during a period of 8 to 10 minutes requires complex machinery embracing a number of distinct cytoskeletal proteins and signaling interventions. Using specific inhibitors, Ubukawa et al added myosin to the other elements, notably tubulin and actin, found in earlier work to be implicated in enucleation.4-7  Of course, many questions remain unanswered including the manner of the spatial and temporal assembly of the various components, and we hope that future work using genetic tools and state-of-the-art imaging techniques will provide more comprehensive insights into this fascinating biologic process and also establish a basis for differences between erythropoiesis in mammals and in other vertebrates.

The allure of this topic is due, at least in large measure, to the special physiologic demands that the mature mammalian red cell has evolved to meet. To fulfill the requirements of shape and flexibility, combined with mechanical stability, the nucleated precursor must dispose of its nucleus.8  This is a problem that evolution has solved, and that is unique to the erythroid system.

Conflict-of-interest disclosure: The author declares no competing financial interests. ■

REFERENCES

REFERENCES
1
Ubukawa
 
K
Guo
 
YM
Takahashi
 
M
, et al. 
Enucleation of human erythroblasts involves non-muscle myosin IIB.
Blood
2012
, vol. 
119
 
4
(pg. 
1036
-
1044
)
2
McGrath
 
KE
Kingsley
 
PD
Koniski
 
AD
Porter
 
RL
Bushnell
 
TP
Palis
 
J
Enucleation of primitive erythroid cells generates a transient population of “pyrenocytes” in the mammalian fetus.
Blood
2008
, vol. 
111
 
4
(pg. 
2409
-
2417
)
3
Keerthivasan
 
G
Small
 
S
Liu
 
H
Wickrema
 
A
Crispino
 
JD
Vesicle trafficking plays a novel role in erythroblast enucleation.
Blood
2010
, vol. 
116
 
17
(pg. 
3331
-
3340
)
4
Koury
 
ST
Koury
 
MJ
Bondurant
 
MC
Cytoskeletal distribution and function during the maturation and enucleation of mammalian erythroblasts.
J Cell Biol
1989
, vol. 
109
 
6 Pt 1
(pg. 
3005
-
3013
)
5
Chasis
 
JA
Prenant
 
M
Leung
 
A
Mohandas
 
N
Membrane assembly and remodeling during reticulocyte maturation.
Blood
1989
, vol. 
74
 
3
(pg. 
1112
-
1120
)
6
Ji
 
P
Jayapal
 
SR
Lodish
 
HF
Enucleation of cultured mouse fetal erythroblasts requires Rac GTPases and mDia2.
Nat Cell Biol
2008
, vol. 
10
 
3
(pg. 
314
-
321
)
7
Liu
 
J
Guo
 
X
Mohandas
 
N
Chasis
 
JA
An
 
X
Membrane remodeling during reticulocyte maturation.
Blood
2010
, vol. 
115
 
10
(pg. 
2021
-
2027
)
8
Mohandas
 
N
Gallagher
 
PG
Red cell membrane: past, present, and future.
Blood
2008
, vol. 
112
 
10
(pg. 
3939
-
3948
)