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Asymmetric cell division in the Drosophila bristle lineage: from the polarization of sensory organ precursor cells to Notch‐mediated binary fate decision

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Abstract Asymmetric cell division (ACD) is a simple and evolutionary conserved process whereby a mother divides to generate two daughter cells with distinct developmental potentials. This process can generate cell fate diversity during development. Fate asymmetry may result from the unequal segregation of molecules and/or organelles between the two daughter cells. Here, I will review how fate asymmetry is regulated in the sensory bristle lineage in Drosophila and focus on the molecular mechanisms underlying ACD of the sensory organ precursor cells (SOPs). WIREs Dev Biol 2015, 4:299–309. doi: 10.1002/wdev.175 This article is categorized under: Nervous System Development > Flies
Regulation of Notch trafficking by Numb in pIIb. Numb (red dots) is specifically segregated into the anterior pIIb cell (left) where it inhibits Notch. Numb relocalizes from the basal cortex of pIIb to apical endosomes where it colocalizes with Notch (blue bars) and sanpodo (green dots). Two models for Numb mode of action have recently been discussed. In a first ‘internalization model’, Numb acts in pIIb to positively regulate, i.e. speed‐up, the internalization of Notch‐Sanpodo oligomers (large green arrow). In a second ‘recycling inhibition model’, Notch‐sanpodo oligomers are internalized in a Numb‐independent manner and Numb acts to inhibit the recycling of Notch and Sanpodo back to the cell surface (red stop sign). Recent experimental evidence favors the ‘recycling inhibition model’ (see text).
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Regulation of cell fate by Numb. (a) The lineage of numb mutant SOPs: defective fate asymmetry results in the specification of two pIIa‐like cells that generate socket‐like cells. (b and b′) In the absence of numb (in a clone of mutant cells positively marked by the expression of a nuclear GFP in green), sensory cells adopt a socket‐like fate: multiple sockets but no shaft are seen at the surface of the fly (arrow). (c–C″) Snapshots of a live imaging movie showing the unequal segregation of Numb in dividing SOPs. The Numb crescent (NumbGFP, green) forms at the anterior cortex of dividing SOPs (marked by Histone2B‐RFP, red, used here as a SOP‐specific mitotic marker). The mitotic spindle (followed here using Asterless‐RFP, red, to mark the centrosomes) rotates to line up along the polarity axis (red arrow in c). At metaphase (c″), the two centrosomes are nicely aligned along the polarity axis such that NumbGFP is specifcally segregated into the anterior pIIb cell (left) at anaphase (c‴). At cytokinesis, the NumbGFP crescent disassembles (c″″) and Numb relocalizes at apical endosomes in pIIb.
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Fate asymmetry is regulated by Notch. (a) The lineage of Notch mutant SOPs: defective fate asymmetry results in the specification of two pIIb‐like cells that generate neuron‐like cells. (b) Notch is ‘ON’ in pIIa and ‘OFF’ in pIIb. Notch receptors in pIIa are activated by ligands present at the surface of the pIIb cell (pink arrows 1 and 2) and/or of neighboring epidermal cells (pink arrow 3). Whether activation of Notch receptors occur apically (1) and/or along the basal cytokinetic furrow (2) remains to be determined. (c) The signaling activity of Notch can be monitored using a functional NotchGFP receptor that allowed the detection of nuclear activated Notch (anti‐GFP, green) in pIIa. Sanpodo (red) is a SOP‐specific protein that localizes mostly at the plasma membrane of pIIa whereas it accumulates in endosomes in pIIb. Note that Notch and Sanpodo co‐accumulate into apical endosomes in pIIb (white arrows in C‴').
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The bristle lineage. (a) Dorsal view of an adult fly, showing the dorsal thorax, or notum, covered with sensory bristles. (b) Electron micrograph showing a bristle shaft (white arrow) and its socket (green arrow) at the base of the shaft. Small hairs mark epidermal cells. (c) Each bristle sensory organ is composed of four cells (sensory organ nuclear marker, blue; socket cell marker, green; internal cell marker, red): the neuron and sheath cells are shown with red arrows, the shaft cell with a white arrow and the socket cell with a green arrow. (d) The sensory bristle lineage: the SOP divides asymmetrically to generate two distinct secondary precursor cells, pIIa (red, Notch ON) and pIIb (blue, Notch OFF). The pIIb cell generates the two internal cells, i.e. the neuron (Notch OFF again) and its associated sheath cell (Notch ON), together with a cell fated to die by apoptosis whereas the pIIa cell produces the two external cells, i.e. the shaft (Notch OFF) and socket (Notch ON again) cells. (e–f″) snapshot views of living pupa (yellow arrow points toward the head in (e) showing all notum cells at 17 h APF. A time series is shown in higher magnification views (f–f″). Histone2A‐RFP (red) marks all epithelial cells. Sensory cells, i.e. SOPs and their pIIb‐pIIa progeny cells, express a nuclear eqFP670 (magenta). SOPs divide along the a–p axis so that pIIb is anterior and pIIa posterior. NumbGFP (green) localizes asymmetrically in dividing SOPs and is inherited by the anterior cell (blue arrows) whereas it is symmetric in dividing epidermal cells (epi; white arrows). Note that sensory organs form a regular pattern of rows. In this and all other figures, anterior is to the left.
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Regulation of Delta endocytosis and signaling by Neuralized in pIIb. Notch (green, at the surface of pIIa) is activated by Delta (red, at the surface of pIIb) in a Neur‐dependent manner. Activation of Notch requires ligand binding (1). The E3 ubiquitin ligase Neur acts in pIIb to add ubiquitin (black) to the intracellular tail of Dl (2). This modified form of Dl is then recognized and targeted for internalization by the endocytic machinery. The internalization of Dl bound to Notch (3) provides a pulling force that alters the conformation of the NRR region of Notch. This conformation change renders the S2 cleavage site accessible to the metalloprotease Kuzbanian (orange). This ligand‐dependent cleavage generates a membrane‐tethered form of Notch that is recognized and cleaved by the γ‐secretase complex (4). This releases the activated form of Notch that acts in the nucleus to regulate gene expression in pIIa.
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Key steps in asymmetric cell division. In a first step, a polarity axis is set up in the mother cell (M), as indicated by the polarized distribution of polarity proteins (red) at the cell cortex prior to mitosis. In a second step, the polarization of cell M leads to the polar distribution of cell fate determinants (blue). In a third step, cortical cues localized along the polarity axis capture astral microtubules and orient the mitotic spindle (green; chromatin in gray) along the polarity axis such that the cell fate determinants are unequally inherited at cytokinesis. In a fourth step, cell fate determinants regulate the binary A versus B cell fate decision.
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Numb anterior localization and orientation of the spindle by PCP and asymmetric aPKC activity. (a) Diagram of a dividing SOP at metaphase. The posterior PCP complex includes Fz and Dsh (light orange). The Baz‐Par6‐aPKC complex (red) also localizes apically at the posterior cortex. Numb (green) and Pins (blue) co‐localize at the anterior basal cortex. Dsh, at the posterior‐apical cortex, and Pins, recruits Mud. Mud interacts with dynein and pulls on astral microtubules to line up the mitotic spindle along the anterior–posterior axis, with a slight anterior basal tilt. (b) At interphase, Lgl inhibits the active Par6‐aPKC complex. Phosphorylation of Par6 by AurA leads to the aPKC‐dependent release of Lgl at mitosis and to the formation of the active Baz‐Par6‐aPKC complex. This complex localizes at the posterior cortex in a PCP‐dependent manner. This complex interacts with Numb, a target of aPKC. Phosphorylated Numb is excluded from the posterior cortex. A similar mechanism may account for the exclusion of Pins from the posterior cortex at mitosis. Thus, PCP provides a spatial input and mitosis provides a temporal input for the asymmetric localization of the Baz‐Par6‐aPKC complex that regulates, together with PCP, both the asymmetric localization of Numb and the orientation of the mitotic spindle.
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