Two of These or Two of Those?
Authors: William A. Harris
Journal: Neuron (2005)

Symmetrically dividing neuroepithelial cells may produce two daughters that are both proliferating or both postmitotic, as highlighted by Zigman et al. in this issue of Neuron and Sanada and Tsai in a recent issue of Cell. Here, I will attempt to offer a simple explanation why these results may be so different. Symmetrically dividing neuroepithelial cells may produce two daughters that are both proliferating or both postmitotic, as highlighted by Zigman et al. in this issue of Neuron and Sanada and Tsai in a recent issue of Cell. Here, I will attempt to offer a simple explanation why these results may be so different. If Danny DeVito had an identical twin, he would probably be shorter than Hulk Hogan's hypothetical identical twin. A symmetrical division of one neural progenitor produces a pair of cells that are like identical twins. A symmetric division of another neural progenitor produces a completely different pair of cells. These pairs are different because their parents are different, Danny's or Hulk's. To help understand how this analogy might be relevant to the difference between the Zigman et al., 2005Zigman M. Cayouette M. Charalambous C. Schleiffer A. Hoeller O. Dunican D. McCudden C.R. Firnberg N. Barres B.A. Siderovski D.R. Knoblich J.A. Neuron. 2005; 48 (this issue): 539-545Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar and the Sanada and Tsai, 2005Sanada K. Tsai L.H. Cell. 2005; 122: 119-131Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar results in the mouse, it may first be useful to look at symmetrical and asymmetrical cell divisions in the Drosophila central nervous system. Drosophila neuroblasts arise from symmetrical divisions of the cells in the horizontal plane of the neurogenic region of the blastoderm. Individual cells in this region, selected as neuroblasts, delaminate from the epithelium and then begin a series of asymmetric apicobasal divisions producing at each division an apical neuroblast (NB) and a basal ganglion mother cell (GMC). The machinery involved in these asymmetric divisions involves proteins that organize into a complex at the apical cortex of the neuroblast (Kaltschmidt and Brand, 2002Kaltschmidt J.A. Brand A.H. J. Cell Sci. 2002; 115: 2257-2264PubMed Google Scholar, Roegiers and Jan, 2004Roegiers F. Jan Y.N. Curr. Opin. Cell Biol. 2004; 16: 195-205Crossref PubMed Scopus (200) Google Scholar, Wang and Chia, 2005Wang H. Chia W. Biol. Cell. 2005; 97: 63-74Crossref PubMed Scopus (27) Google Scholar). A key component of this complex is the membrane-associated Inscuteable (Insc) protein. Insc binds to Par-3/Par-6/aPKC and Partner of Inscuteable (aka Pins). Pins then binds to Gαi, leading to the local activation of heterotrimeric G proteins, particularly Gβγ, that attracts one of the two centrioles, thus orienting the plane of division along the apicobasal axis (David et al., 2005David N.B. Martin C.A. Segalen M. Rosenfeld F. Schweisguth F. Bellaiche Y. Nat Cell Biol. 2005; 7: 1083-1090Crossref PubMed Scopus (109) Google Scholar, Izumi et al., 2004Izumi Y. Ohta N. Itoh-Furuya A. Fuse N. Matsuzaki F. J. Cell Biol. 2004; 164: 729-738Crossref PubMed Scopus (86) Google Scholar, Wang and Chia, 2005Wang H. Chia W. Biol. Cell. 2005; 97: 63-74Crossref PubMed Scopus (27) Google Scholar, Yu et al., 2003Yu F. Cai Y. Kaushik R. Yang X. Chia W. J. Cell Biol. 2003; 162: 623-633Crossref PubMed Scopus (99) Google Scholar). The different fates of the apical NB and the basal GMC are tied to the differential inheritance of cytoplasmic determinants, Numb and Prospero, located at the basal pole of the parental NB at the moment of cytokinesis. Numb is a negative regulator of the Notch pathway, and Prospero is a homeodomain transcription factor (Knoblich et al., 1995Knoblich J.A. Jan L.Y. Jan Y.N. Nature. 1995; 377: 624-627Crossref PubMed Scopus (421) Google Scholar). The asymmetric inheritance of these two proteins differently affects the fates and proliferative potentials of the NB and the GMC. GMCs do not divide apicobasally; they divide in the horizontal plane to produce two postmitotic daughters. The Drosophila situation is remarkably similar to neuroepithelial cells in the mammalian cortex. At early stages, these cells tend to divide symmetrically, giving rise to two dividing progenitor cells, but as neurogenesis proceeds, some neuroepithelial cells begin to divide asymmetrically: one neuroepithelial progenitor and one differentiated neuron. Toward the end of neurogenesis, symmetrical cell divisions predominate again, producing two postmitotic neurons (Cai et al., 2002Cai L. Hayes N.L. Takahashi T. Caviness Jr., V.S. Nowakowski R.S. J. Neurosci. Res. 2002; 69: 731-744Crossref PubMed Scopus (54) Google Scholar). Time-lapse observations of neuroepithelial cells in organotypic slices of the developing mammalian cortex show that divisions along the horizontal plane produce two cells that stay in contact with the ventricular surface, whereas more apicobasal divisions produce a basal daughter that migrates away from the ventricular surface while the other daughter remains in contact, consistent with it retaining a neuroepithelial fate (Chenn and McConnell, 1995Chenn A. McConnell S.K. Cell. 1995; 82: 631-641Abstract Full Text PDF PubMed Scopus (650) Google Scholar). These interesting similarities between Drosophila and mammalian neurogenesis have attracted vertebrate workers to search for homologs of the Drosophila genes involved in asymmetric cell divisions (reviewed in Huttner and Kosodo, 2005Huttner W.B. Kosodo Y. Curr. Opin. Cell Biol. 2005; 17: 648-657Crossref PubMed Scopus (200) Google Scholar). In the two papers highlighted in this preview, Sanada and Tsai, 2005Sanada K. Tsai L.H. Cell. 2005; 122: 119-131Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar interfere with Gβγ and ASG3, a mammalian homolog of Pins, while Zigman et al., 2005Zigman M. Cayouette M. Charalambous C. Schleiffer A. Hoeller O. Dunican D. McCudden C.R. Firnberg N. Barres B.A. Siderovski D.R. Knoblich J.A. Neuron. 2005; 48 (this issue): 539-545Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar clone and then interfere with a mammalian Insc homolog. Sanada and Tsai, 2005Sanada K. Tsai L.H. Cell. 2005; 122: 119-131Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar used the carboxy terminus of the β-adrenergic receptor kinanse (βARK-ct) to block Gβγ signaling in the mouse cortex, which leads to the loss of spindle orientation along the apicobasal axis. Neuroepithelial cells misexpressing βARK-ct not only have more planar divisions, they also exit the cell cycle early and produce pairs of neurons (Figure 1). In vivo, these overexpressing βARK-ct cells migrate away from the ventricular zone and into the intermediate zone and cortical plate, indicating that they give rise to early differentiating neurons. They obtain similar results by knocking down the Pins homolog, ASG3, by electroporation of RNAi. Zigman et al., 2005Zigman M. Cayouette M. Charalambous C. Schleiffer A. Hoeller O. Dunican D. McCudden C.R. Firnberg N. Barres B.A. Siderovski D.R. Knoblich J.A. Neuron. 2005; 48 (this issue): 539-545Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar examine the retina rather than the neocortex. They show that the mInsc protein localizes to the apical pole of retinal progenitors and that knocking down mInsc using retroviral infection of short hairpin RNAi causes retinal progenitors to divide preferentially in the horizontal plane and produce larger clones. If allowed to mature in vivo, these clones show an excess of bipolar cells, the last-born neural cell type in the mouse retina. The question is why are the final results of these two studies so different? One possibility is that it has something to do with numb. It is well known that the lateral inhibition through the Notch pathway is responsible for generating differential fates at many points in a cell lineage. The most well known example is the Drosophila sensory organ precursor lineage, where loss of numb or interference with Notch signaling at different points leads to both daughters adopting symmetrical fates either as spIIb progenitors, sensory neurons, or bristle shaft cells, depending on where in the lineage tree Notch signaling is disturbed (Schweisguth et al., 1996Schweisguth F. Gho M. Lecourtois M. Dev. Genet. 1996; 18: 28-39Crossref PubMed Scopus (31) Google Scholar). The apical localization of mammalian numb, a regulator of Notch signaling, may thus have strikingly different effects on cell fates depending where in the lineage it is differentially inherited. Mouse numb knockouts suggest that numb is essential for the cortical neuroepithelial cells to remain in a progenitor sate (Petersen et al., 2002Petersen P.H. Zou K. Hwang J.K. Jan Y.N. Zhong W. Nature. 2002; 419: 929-934Crossref PubMed Scopus (282) Google Scholar). Studies in the rat retina late in neurogenesis, however, show that the inheritance of numb does not favor cells remaining in the cell cycle. In horizontal divisions, where both daughters inherit numb, they often both differentiate into the same type of cells, such as photoreceptors, a fate that is also promoted by overexpression of numb, whereas the asymmetric distribution of numb in the these cells correlates with different postmitotic fates (Cayouette and Raff, 2003Cayouette M. Raff M. Development. 2003; 130: 2329-2339Crossref PubMed Scopus (124) Google Scholar). Numb is only one of many determinants that could be symmetrically or asymmetrically partitioned according to the orientation of cell division. Thus, it is not much of a leap to imagine that the symmetric versus asymmetrical inheritance of numb, or perhaps other determinants, might have very different consequences in the retinal versus neocortical lineages. The key point here is that the featured studies show that the orientation of division does have a role in determining cell fate in the developing mammalian nervous system, as it does in Drosophila. But that role is different in different lineages. Thus, decreasing apicobasal division increases symmetrical fates, even though these fates might be very different in distinct regions of the nervous system that are undergoing different (Danny DeVito- or Hulk Hogan-generating) lineage programs.