The development of the mammalian neocortex involves rounds of symmetric and asymmetric cell division of neural progenitors to fulfill needs of both self-renewal of progenitors and production of differentiated progenies such as neurons and glia. The machinery for asymmetric cell division is evolutionarily conserved and extensively used in organogenesis and homeostasis of adult tissues. Here we summarize recent progress regarding cellular characteristics of different types of neural progenitors in mammals, highlighting how asymmetric cell division is utilized during cortical development.
. Cortical development and asymmetric cell divisions[J]. Frontiers in Biology, 2012, 7(4): 297-306.
Yan ZHOU. Cortical development and asymmetric cell divisions. Front Biol, 2012, 7(4): 297-306.
After delamination of the neuroblast from the neuroepithelium, Bazooka provides an asymmetric cue in the apical cytocortex that is required to anchor Inscuteable. Bazooka is also responsible for the maintenance of apical-basal polarity in epithelial tissues (Kuchinke et al., 1998; Schober et al., 1999).
mPar3
1) mPar3 is enriched at the lateral membrane domain in the ventricular endfeet of RG cells during interphase, whereas it becomes dispersed and shows asymmetric localization during mitosis. mPar3 acts through the Notch signaling pathway in generating the asymmetry in radial glial daughter cell fate specification (Bultje et al., 2009).2) Specifies axon-dendrite polarity in hippocampal neurons (Shi et al., 2003).
Par6
Sets up apico-basal polarity. Loss of Par-6 leads to defects in the apical localization of Baz and Insc in neuroblasts and defects in the basal localization of Numb and Miranda, as well as the randomization of neuroblast spindle orientation; its loss also leads to defects in epithelial polarity (Petronczki and Knoblich, 2001).
Par6 (Pard6A)Pard6BPard6G
1) Par6 specifies axon-dendrite polarity in hippocampal neurons (Shi et al., 2003).2) Par6 Controls glial-guided neuronal migration (Solecki et al., 2004).3) Par6 overexpression promotes the generation of RG cells in vitro and in vivo (Costa et al., 2008).
aPKC
Sets up apico-basal polarity. aPKC mutation results in loss of apico-basal polarity, multilayering of epithelia, mislocalization of Insc, and abnormal spindle orientation in neuroblasts (Wodarz et al., 2000; Rolls et al., 2003).
aPKCλ & aPKCζ
aPKCλ is required for the maintenance of adherens junctions between endfeet of RG cells. In conditional aPKCλ knockout mice, adherens junctions are lost but neurons were produced at a normal rate (Imai et al., 2006).
Lgl
Controls basal localization of cell-fate determinants(Ohshiro et al., 2000; Peng et al., 2000).
Lgl1
Maintains cell polarity of RG cells. Loss of Lgl1 in mice results in formation of neuroepithelial rosette-like structures. A large proportion of Lgl1–/– neural progenitor cells fail to exit the cell cycle and differentiate, but continue to proliferate and die by apoptosis. Dividing Lgl1–/– cells are unable to asymmetrically localize Numb (Klezovitch et al., 2004).
Mitotic spindle positioning
Insc
Inscuteable tethers together the Par and Pins complexes at the apical side. Loss of Insc results in misoriented mitotic spindles and randomized crescents of determinants. Ectopic expression of Insc in epithelial cells triggers a reorientation of the mitotic spindle into an apical-basal direction (Kraut et al., 1996).
mInsc
Orients mitotic spindles in retinal progenitors and RG cells:1) In rat retinal explants, downregulation of mInsc inhibits vertical divisions and leads to proliferation and cell fate specification defects (Zigman et al., 2005).2) Loss of mInsc results in defects of neurogenesis and depletion of basal progenitors. mInsc overexpression leads to expansion of basal progenitors (Postiglione et al., 2011).
Pins
Pins and Inscuteable are dependent on each other for asymmetric localization in neuroblasts. In Pins mutants, neuroblasts showed defects in the orientation of their mitotic spindle and the basal asymmetric localization of Numb and Miranda (Schaefer et al., 2000; Yu et al., 2000).
LGN(Gpsm2)
Maintains planar divisions and RG cell fates.Knocking out LGN randomized the orientation of normally planar divisions of RG cells. The resultant loss of the apical membrane from daughter cells converted them into abnormally localized progenitors without affecting neuronal production rate (Konno et al., 2008).
Ags3(Gpsm1)
Receptor-independent activators of Gβγ signaling. Regulates spindle orientation and asymmetric cell fate of RG cells (Sanada and Tsai, 2005).
Hetero-trimeric G proteins
The signaling mediated by the Gβ subunit of heterotrimeric G proteins determines asymmetric spindle formation. Lack of Gβ induces a large symmetric spindle and causes division into nearly equal-sized cells with normal segregation of the determinants (Fuse et al., 2003).Interfering with G protein function by Gαi overexpression or depletion of heterotrimeric G protein complexes causes defects in spindle orientation and asymmetric localization of determinants (Schaefer et al., 2001).
Hetero-trimeric G proteins
Interfering with Gβγ function in mouse neural progenitors causes a shift in spindle orientation from apical-basal divisions to planar divisions. This results in overproduction of neurons as a consequence of both daughter cells adopting the neuronal fate (Sanada and Tsai, 2005).
Cell fate determination
Miranda
Directs the basal cortical localization of multiple molecules, including Staufen and prospero RNA, in mitotic neuroblasts in an actin-dependent manner(Ikeshima-Kataoka et al., 1997; Shen et al., 1997).
N/A
N/A
Numb
1) Specifies cell fates in the development of central and peripheral nervous system and myogenic lineage by antagonizing Notch signaling (Rhyu et al., 1994; Knoblich et al., 1995; Ruiz Gómez and Bate, 1997).2) Numb mutation results in overproliferation of neuroblasts and tumor formation in larval brain (Bowman et al., 2008).
Numb &Numbl
1) Numb and Numbl are redundant in asymmetric cell-fate specification of neural precursors.2) Numb loss leads to depletion or hyperproliferation of neural progenitor cells in different genetic settings (Petersen et al., 2002; Li et al., 2003; Petersen et al., 2004).3) Numb may be also required for maintenance of cadherin-based adhesion and polarity of RG cells (Rasin et al., 2007).
Prospero
As a homeodomain-containing transcription factor, prospero represses genes required for self-renewal and activates genes for terminal differentiation. Loss of prospero causes neuroblast overproliferation (Doe et al., 1991; Choksi et al., 2006).
Prox1 & Prox2
1) Inhibit progenitor cell proliferation and promote horizontal cell genesis in the mouse retina (Dyer et al., 2003).2) Prox1 mediates suppression of Notch1, thus relieves Notch’s inhibition on neurogenesis and allows NPCs to exit the cell cycle and differentiate in chick and mouse spinal cords (Kaltezioti et al., 2010).
Staufen
Mediates asymmetric localization and segregation of prospero RNA but not of Pros protein (Li et al., 1997; Broadus et al., 1998).
Stau1 & Stau2
Both are RNA binding proteins. Stau1 mediates mRNA decay including mRNA of ADP-ribosylation factor-1 (ARF1) (Kim et al., 2005; Gong and Maquat, 2011; Cho et al., 2012).
Brat
Promotes neuronal differentiation and inhibits neuroblast self-renewal by inhibiting dMyc (Betschinger et al., 2006; Lee et al., 2006).
Trim32
Induces neuronal differentiation by inhibiting c-Myc and activating let-7 (Schwamborn et al., 2009).
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