The Simple Life (of Cortical Progenitors)Selected ReadingNeuron, Vol. 45, 817–823, March 24, 2005, Copyright ©2005 by Elsevier Inc.Previewsdeterminants have been described, including transcrip-The Simple Lifetional activators and repressors, as well as molecules(of Cortical Progenitors)that regulate their asymmetric localization and/or ex-pression (Betschinger and Knoblich, 2004). Asymmetri-cally distributed molecules regulate other kinds ofmolecules important for cell fate; for example, asym-Asymmetric cell division plays a major role in themetric Numb, Neuralized, and α-adaptin regulate thegeneration of cell diversity during development. InNotch protein, which serves to regulate a cell's respon-this issue of Neuron, Sun and colleagues present evi-siveness to external signals (Betschinger and Knob-dence that the epidermal growth factor receptor islich, 2004).asymmetrically distributed in mitotic cerebral corticalThe ability of a cell to respond to its environment canprecursors, and the resulting unequal inheritanceplay a major role during differentiation. The timing ofgenerates offspring with different responsiveness todifferentiation during neuronal development in the Dro-growth factor and unique cell fates.sophila eye appears to be tightly coordinated with ex-trinsic growth signals (Bateman and McNeill, 2004).Our ability to acquire and use limited resources playsEGFR plays multiple roles in cell fate determination dur-an important role during our development. Even whening eye development, and its activation is regulated bywe grow up in the same environment, differences inlocalized presentation of ligand (Perrimon and Perkins,how we exploit our surroundings can shape our futures.1997). In mammals as well, cell fate can be regulated byMight we have grown taller had we consumed the lastresponsiveness to external signals and growth factorsglass of milk that was instead seized by our siblings?such as EGF. In the developing cortex, the choice be-Some of the factors that regulate how well we obtaintween proliferation and differentiation is influenced byor utilize what is available may be intrinsic, such as hav-EGFR expression in cortical precursors and extracellu-ing a better sense of smell or fondness for dairy prod-lar ligand concentration (Burrows et al., 1997). Togetheructs. Much like us, sibling cells in developing animalswith the observations in Drosophila, these findings sug-might not necessarily begin life equally. Recent workgested that responsiveness to environmental signalsby Sun et al. shows that the fate of mammalian neuralcan be regulated by limiting expression of receptorsprecursor siblings can be determined by the amount ofsuch as the EGFR and raised the possibility that combi-epidermal growth factor receptor (EGFR) inherited atnations of receptor and ligand levels could regulate celltheir births, and their ability to respond to epidermalfate decisions in the developing mammalian brain.growth factor depends on how much EGFR they haveNot surprisingly, growing evidence suggests that cellwhen they begin life (Sun et al., 2005 [this issue offate decisions in the development of the mammalianNeuron]).cerebral cortex utilize similar mechanisms to thoseVariations on two basic themes can be used to estab-found in invertebrates. Mouse Numb and Numblikelish differences between cells. From the moment of(Numbl), the homologs of Drosophila numb, appear totheir birth following a cell division, sibling cells can beregulate neuronal and progenitor number (Castaneda-either identical or different. Initially, identical cells mightCastellanos and Kriegstein, 2004), and imaging of di-encounter different environmental cues and conse-viding mammalian neural precursors in slices of de-quently develop differently. In contrast, differences be-veloping cerebral cortex (Chenn and McConnell, 1995)tween two daughters can be generated through intrinsi-and in utero (Haydar et al., 2003) suggested that mitoticcally asymmetric cell division, or divisions that resultorientation of cortical progenitors could predict cellimmediately in two distinct offspring. Intrinsically asym-fate. Targeted mutations in the Lis1 interacting proteinmetric cell divisions occur during the development ofNde1 caused disrupted mitotic spindle orientation andmany organisms. The molecular details of asymmetricdecreased neuronal production, leading to the proposaldivision are best understood in Drosophila melanogas-that the loss of spindle orientation altered neuronal fateter, Caenorhabditis elegans, and Saccharomyces cere-decisions (Feng and Walsh, 2004). Whether these mi-visiae, where asymmetric division results from an initialtotic orientation changes resulted in changes in divisionestablishment of cell polarity, subsequent localizationsymmetry remain an intriguing possibility, and howof specific molecules to one pole of the mitotic cell, andsuch changes in division symmetry might lead toasymmetric inheritance of these molecules following anchanges in mammalian precursor cell fate decisionsoriented mitotic cleavage (Jan and Jan, 2000).await further study.Although the factors that regulate cell diversity areThis current study by Sun and colleagues providescomplex, a wealth of evidence from worms and fliesone possible mechanism by which asymmetric divi-suggests that early neural cell fate is regulated by in-sions might regulate cell fate decisions in developingtrinsic differences between sibling cells that arise fromcortical precursors. Examining sections through the de-asymmetric divisions. Asymmetric distribution of deter-veloping forebrain, they found that the EGFR wasminants can regulate whether a precursor generatesasymmetrically distributed in approximately one-fifth ofadditional multipotent precursors, more differentiatedmitotic progenitor cells that expressed EGFR. Elegantprecursors with more restricted potential, or differenti-in vitro studies of single cortical progenitor cells indi-cated that even in progenitor cells isolated from theated progeny. A variety of asymmetrically distributedNeuron818Figure 1. Potential Similarities between Nor-mal Cortical Development and Brain TumorDevelopment(Left) Asymmetric distribution of EGFR (redcrescent) in dividing cortical precursor givesrise to one daughter expressing high levelsof EGFR and one daughter expressing lowlevels. The EGFRhighdaughter also ex-pressed the radial glial marker RC2 andgives rise to astrocytes, while the EGFRlowdaughter is RC2 negative and generates