Hippenmeyer et al., 2010 Hippenmeyer S.

Youn Y.H.

Moon H.M.

Miyamichi K.

Zong H.

Wynshaw-Boris A.

Luo L. Genetic mosaic dissection of Lis1 and Ndel1 in neuronal migration.

Joo et al., 2014 Joo W.

Hippenmeyer S.

Luo L. Neurodevelopment. Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling.

Bayraktar et al., 2014 Bayraktar O.A.

Fuentealba L.C.

Alvarez-Buylla A.

Rowitch D.H. Astrocyte development and heterogeneity.

Kriegstein and Alvarez-Buylla, 2009 Kriegstein A.

Alvarez-Buylla A. The glial nature of embryonic and adult neural stem cells.

Ge et al., 2012 Ge W.P.

Miyawaki A.

Gage F.H.

Jan Y.N.

Jan L.Y. Local generation of glia is a major astrocyte source in postnatal cortex.

Gao et al., 2014 Gao P.

Postiglione M.P.

Krieger T.G.

Hernandez L.

Wang C.

Han Z.

Streicher C.

Papusheva E.

Insolera R.

Chugh K.

et al. Deterministic progenitor behavior and unitary production of neurons in the neocortex.

Gao et al., 2014 Gao P.

Postiglione M.P.

Krieger T.G.

Hernandez L.

Wang C.

Han Z.

Streicher C.

Papusheva E.

Insolera R.

Chugh K.

et al. Deterministic progenitor behavior and unitary production of neurons in the neocortex.

Molofsky et al., 2014 Molofsky A.V.

Kelley K.W.

Tsai H.H.

Redmond S.A.

Chang S.M.

Madireddy L.

Chan J.R.

Baranzini S.E.

Ullian E.M.

Rowitch D.H. Astrocyte-encoded positional cues maintain sensorimotor circuit integrity.

Molofsky and Deneen, 2015 Molofsky A.V.

Deneen B. Astrocyte development: a guide for the perplexed.

Müsch et al., 2002 Müsch A.

Cohen D.

Yeaman C.

Nelson W.J.

Rodriguez-Boulan E.

Brennwald P.J. Mammalian homolog of Drosophila tumor suppressor lethal (2) giant larvae interacts with basolateral exocytic machinery in Madin-Darby canine kidney cells.

Zhang et al., 2016 Zhang Y.

Sloan S.A.

Clarke L.E.

Caneda C.

Plaza C.A.

Blumenthal P.D.

Vogel H.

Steinberg G.K.

Edwards M.S.

Li G.

et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse.

MADM is a powerful approach to study cell-autonomous gene function at high spatiotemporal resolution (). Here, the analysis of Lgl1-MADM allowed us to identify as-yet-unknown cell-autonomous Lgl1 functions in NSC proliferation behavior ( Figure 8 ). Once RGPs cease the production of projection neurons, they adopt gliogenic potential (). However, the cellular and molecular mechanisms controlling glia production and quantitative output are not well understood. In our analysis of Lgl1-MADM, we discovered that the production of astrocytes is strongly increased upon cell-autonomous loss of Lgl1. Interestingly, the relative number of astrocytes was also significantly higher in cKO-Lgl1-MADM indicating a dominant cell-autonomous component, not strongly influenced by non-cell-autonomous community effects. What can we learn from the Lgl1 loss-of-function astrocyte phenotype with regard to the general principles of RGP proliferation behavior? It has been suggested that RGPs give rise to aIPCs that locally amplify astrocyte production in a tightly controlled manner (). It is currently not clear whether astrocyte production follows a strictly deterministic program similar to neurogenic RGPs () or whether a certain degree of stochasticity contributes to the proliferation dynamics of aIPCs. Regardless of the precise mechanism, clonally related astrocytes do not disperse broadly (), and because astrocytes exhibit precise tiling (i.e., do not overlap their fine projections), it has been suggested that astrocyte production is controlled by homeostatic cues to ensure complete coverage of the local neuropil (). In any case, loss of Lgl1 function results in a scalable overproduction of Lgl1astrocytes. Given that astrocytes tile the neuropil, do Lgl1aIPCs have a competitive advantage over WT progenitors? And if yes, which Lgl1-dependent signaling cascades are misregulated in aIPCs? The astrocyte overproduction in Lgl1-MADM could reflect the loss of a specific Lgl1-dependent function in polarized secretion and/or exocytosis in order to regulate cell-surface abundance of astrocyte production stimulating and/or inhibiting factors. It is intriguing to note that the control of polarized secretion, exocytosis (), and possibly further intracellular trafficking events, could actually represent one unifying function of Lgl1 in the control of proliferating NSCs. In such a mechanistic framework, Lgl1 could regulate the cell-surface abundance of junctional complex components in embryonic RGPs, control trafficking events critical for cytokinesis in type B1 NSC, and tune growth factor receptor levels at the plasma membrane in proliferating aIPCs. In this regard, we could observe genetic interaction between Lgl1 and Egfr suggesting, indeed, a functional relationship. Although the precise nature of Lgl1/Egfr interaction remains to be determined, it seems highly specific for cortical astrocyte generation but not V-SVZ NSC behavior ( Figure S8 ). It will be revealing to probe whether LGL1 and EGFR interact at the protein level and to assay EGFR cell surface levels and/or turnover in Lgl1context during astrocyte generation. We cannot exclude that Egfr and Lgl1 also play independent functions in astrocyte generation, and it will be interesting to dissect those putative functions. Alternatively, but not mutually exclusive, Lgl1 could regulate the number of symmetric amplification versus asymmetric differentiation divisions by regulating intracellular polarity and/or the symmetry of the division plane in aIPCs. It will be interesting in the future to assess the mechanisms and dependence on Lgl1 function dictating the total astrocyte unit production in distinct functional areas in the cortex and beyond in other brain areas. Lastly, Lgl1 is highly expressed in mature astrocytes (), and it will be intriguing to assess the expression status of Lgl1 in reactive astrocytes during injury and whether the local response in quiescent astrocyte progenitors require the downregulation and/or inhibition of Lgl1 function in order to initiate the astrocyte production at injury sites.