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Microtubule-destabilizing domain of Cenpj is required for migration. (a–e) Analysis of radial migration in cortices 3 days after co-electroporation of GFP with a control shRNA (a), Cenpj shRNA alone (b), Cenpj shRNA together with a full-length Cenpj expression construct (pCMV-Cenpj, c), Cenpj shRNA with a truncated Cenpj construct lacking the microtubule-destabilizing domain PN2-3 (pCMV-Cenpj dPN2-3, d) or Cenpj shRNA with a truncated Cenpj construct lacking the domain TCP (pCMV-Cenpj dTCP, e). Scale bar, 50 μm. (f,g) Quantification of the migration defects of GFP+ cells in the different zones of the cortex. The migration defect of Cenpj-depleted cells is rescued by overexpression of full-length Cenpj (f) and Cenpj dTCP but not of Cenpj dPN2-3 (g). Student’s t-test *P<0.05; **P<0.01; ***P<0.001. (h–l) Analysis of leading process thickness in neurons in the CP co-electroporated with GFP and Control shRNA (h), with Cenpj shRNA (i) and Cenpj shRNA and Cenpj full length (j) or Cenpj shRNA and Cenpj dPN (K) or Cenpj shRNA and Cenpj dTCP (l). Scale bar, 5 μm. (m) Quantification of leading process thickness in GFP+ neurons. The leading process enlargement observed in Cenpj-depleted neurons is rescued by co-expression of Cenpj shRNA with Cenpj full length and Cenpj dTCP but not by Cenpj dPN. Three embryos analysed for each condition; control shRNA, n=177 cells; Cenpj shRNA, n=200 cells; Cenpjsh+Cenpj FL, n=157 cells; Cenpj shRNA +Cenpj dPN2-3, n=274 cells; Cenpj shRNA+Cenpj dTCP, n=211 cells. Student’s t-test ***P<0.001. DAPI, 4',6-diamidino-2-phenylindole.
Source publication
The proneural factor Ascl1 controls multiple steps of neurogenesis in the embryonic brain, including progenitor division and neuronal migration. Here we show that Cenpj, also known as CPAP, a microcephaly gene, is a transcriptional target of Ascl1 in the embryonic cerebral cortex. We have characterized the role of Cenpj during cortical development...
Citations
... These large datasets increase the sensitivity of our measurements, allowing us to detect minimal yet significant changes in MT dynamic signatures. Our computational approach has revealed novel organizational and regulatory patterns in MT homeostasis, initially in renal cell carcinoma 5 , and has begun to impact studies on a wide range of topics in cell and cancer biology [43][44][45][46][47][48][49][50][51][52][53][54][55] . ...
(See also the 8 PDF files appended below) The treatment of prostate cancer (PCa) has been impeded by the lack of clinically relevant disease models. There are only three PCa cell lines as available models of this heterogeneous disease out of the over 1,000 publicly available cancer cell lines; patient-derived
xenografts (PDX) have proven rarely possible to establish thus far. My previous work in PCa cell lines has demonstrated that we can associate the alterations in a particular parameter of microtubule (MT) dynamics to taxane resistance in ERG overexpressing cells. MT regulating genes such as chTOG, CLIP170, MAP4, MCAK, TPX2 and Op18 to name a few are implicated in the process of conferring drug resistance and susceptibility. Because these genes are also involved in the regulation of MT dynamics, my central hypothesis is that computational analysis of MT dynamics (MT signature) can serve as a real-time readout of cell susceptibility to drug action, which will allow to discover mechanisms of resistance. Therefore, to test my hypotheses in patient-derived cells, I propose to perform two specific aims in patient-derived PCa organoids: Specific Aim 1: Define and validate cancer-specific MT dynamics signatures of MT-targeting agents (MTA) resistance. I will image and measure endogenous and drug-induced signatures (consisting of 12 descriptive parameters) of MT dynamics alterations in patient-
derived cancer organoids using ClusterTrack. For each organoid type, I will measure populations of cells before and after treatment with MTAs, and will perform statistical analysis. I will use, as a
starting point, samples with known patient treatment outcome for specific MTAs (Docetaxel, Cabazitaxel, Eribulin, etc.), which will allow me to validate the MT signatures and classify them into
sensitive and resistant groups using clustering. Specific Aim 2: Define cancer-specific molecular mechanisms of MTA resistance to elucidate targeting strategies. I will extract RNA and will perform differential expression analysis of MT regulators in patient-derived cancer organoids as well as pathway analysis using iPAGE. I will correlate the RNA-seq MT signatures to the validated MT dynamics signatures obtained in Aim 1 using pattern matching. Correlated signatures will contain multiple up- or down-regulated MT regulator genes. I will test the proteins in these lists as candidates for personalized targets in knockdown and overexpression experiments. This approach could identify novel candidates for effective targeted therapies in metastatic disease within the MT-interacting transcriptome. I will further test these novel organoids into PDX models of PCa to confirm sensitization and therapeutic susceptibility in vivo. Further validation, of both prognostic and predictive markers, will be done by comparing ex vivo tumor growth kinetics and treatment predictions to outcomes of patients with similar genetic profiles, after drug treatment, enrolled in clinical trials. See: github.com/amatov/SegmentationBiomarkerCTC,
github.com/amatov/AntibodyTextureMorphology,
github.com/amatov/DataSetTracker
... These large datasets increase the sensitivity of the assay, allowing us to detect very small yet significant changes in MT dynamic signatures. Our computational approach has revealed novel organizational and regulatory patterns in MT homeostasis (initially in renal cell carcinoma 40 ) and has begun to impact studies on a wide range of topics in cell and cancer biology [41][42][43][44][45][46][47][48][49][50][51][52][53] . Our main objective in this proposal is to elucidate the various mechanisms of resistance by (i) classifying these signatures based on patient treatment outcome to investigate individual mechanisms of resistance to MT chemotherapy. ...
(See also the 7 PDF files appended below) In the summer of 2007, ClusterTrack software, an approach that I conceived based on a hypothesis I formulated in 2005, allowed for the first time comprehensive measurements of microtubule behavior, encompassing all cellular areas, including the cell body, where the density of the cytoskeleton is high. Additionally, the ClusterTrack algorithm allowed for the characterization of the different stages of microtubule depolymerization, a process that cannot be visualized using existing molecular markers. Using this software, I
directly measured two parameters of microtubule dynamics and computationally inferred another ten parameters to evaluate a microtubule dynamics signature. This computational approach could evaluate and compare the effects of both established and new microtubule targeting agents on microtubule dynamics. In the
long run, dissecting the mechanisms of microtubule organization using this computing tool will allow better drugs to be designed by exploiting cancer-specific aberrations and aid in the characterization of new therapies that combine cytotoxic chemotherapy with small molecules to eliminate residual disease and impede relapse. Every aspect of tubulin dynamicity in living cells is controlled by multiple genes, whose up- or down-regulation is linked to resistance to therapy. About 70 microtubule-associated proteins and 80 proteins within the kinetochore complex can be targeted in RNA therapy. Microtubule regulators, GKS3β, TPX2, chTOG, KIF2C, MAP2, CLIP170, etc., are implicated in conferring drug resistance and pathogenesis. The expression levels of these genes can serve as a readout of susceptibility to drug action and as personalized targets. RNA therapy can (i) sensitize tumors to existing regimens or (ii) explore novel targets within the microtubule transcriptome. See:
github.com/amatov/InstantaneousFlowTracker, github.com/amatov/ClusterTrackTubuline,
github.com/amatov/DyneinFunctionAnalysis,
github.com/amatov/SegmentationBiomarkerCTC,
github.com/amatov/AutomatedBlotQuantification, github.com/amatov/DataSetTracker
... These large datasets increase the sensitivity of the assay, allowing to detect very small yet significant changes in MT signatures. My computational approach has revealed novel organizational and regulatory patterns in MT homeostasis (initially in renal cell carcinoma 3 ) and has begun to impact studies on a wide range of topics in cell and cancer biology 1,[42][43][44][45][46][47][48][49][50][51][52][53] . Of all solid tumors, BC is the disease with the highest number of MTAs approved, consisting of seven stabilizing and destabilizing MTAs, highlighting that MT targeting is impactful and yet, suggesting there is variability in patient response. ...
(See also the 8 PDF files appended below) This work is based on a hypothesis I formulated in 2006 pertaining to targeting particular aspects of microtubule dynamics for cancer treatment. Thereafter, my goal was to investigate breast cancer-specific aberrations at the cellular level. The microtubules are essential polymer filaments composed of tubulin subunits that organize and rearrange the interior of the cell. They play indispensable roles in several cellular processes such as migration, mitosis, and internal transport processes critically involved in cancer metastasis and proliferation. The microtubules are structurally stiff but dynamic. Their tendency to rapidly extend and retract in a stochastic way is termed dynamic instability of microtubule plus end tips. This dynamicity allows a cell to utilize microtubules in diverse functional contexts, one of which is mitosis. Microtubule rearrangement and cytoskeletal reorganization allow cells to assemble mitotic spindles. Within the spindles, the microtubules undergo a process termed treadmilling during which their plus ends are located in proximity to the chromosomes at the metaphase plate, where microtubules add dimers or polymerize, while their minus ends are located outward toward the two poles, from where the microtubules remove dimers or depolymerize at similar rates. These microtubule-based structures align duplicated chromosomes near the cell center and ultimately segregate the copies into each of the daughter cells. In interphase, microtubules are the freeways of the cellular transport infrastructure. Failure to maintain the appropriate microtubule cytoskeletal network during interphase or spindles with normal size and regulation during mitosis are hallmarks of disease. Further, the signaling molecules that interact with microtubules, as well as the multiple effects on signaling pathways that destabilize or hyper-stabilize microtubules, indicate that microtubules are likely to be critical to the spatial organization of signal transduction. How players in these pathways are positioned spatially and how signals travel within the intracellular environment from the cell surface to the nucleus or other cytoplasmic targets is poorly understood. The microtubules are also affected by signaling pathways, which contributes to the transmission of signals to downstream targets. The microtubule cytoskeleton is often targeted during treatment of metastatic solid tumors and breast cancer in particular, and the microtubules are one of the most validated targets in oncology due to the clinical efficacy of taxanes, vinca alkaloids and other tubulin inhibitors (e.g., epothilones, eribulin) in a wide range of degenerative diseases. Some microtubule-targeting agents bind to individual tubulin dimers and block tubulin polymerization (microtubule-destabilizing agents); others bind to the lattice of microtubules and inhibit microtubule ability to depolymerize (microtubule-stabilizing agents). For some cancers, several chemical compounds that disrupt the homeostasis of the microtubule cytoskeleton are used clinically, suggesting that targeting tubulin might be impactful, yet, there is large variability in patient response. Despite improvements in the diagnosis and therapy of many types of breast cancer, many aggressive forms, such as receptor triple-negative cancers, are associated with the worst patient outcomes; though initially effective in reducing tumor burden for some patients, acquired resistance to cytotoxic chemotherapy is almost universal, and there is no rationale for identifying intrinsically drug-resistant and drug-sensitive patient populations before initiating therapy. I performed high-resolution live-cell imaging of 12 cell lines with labeled microtubules. During cell division, the receptor triple-negative MDA-MB-231 mitotic spindles were the largest. They exhibited rapid lateral twisting during metaphase (see videos with examples of rotating spindles at vimeo.com/382125072/bce76f2ef0 and vimeo.com/382256739/ccd8ab1b63), which remained unaffected by knockdown of the oncogene Myc and treatment with inhibitors of the serine/threonine-protein kinase B-Raf and the epidermal growth factor receptor, alone or in any combination. The MDA-MB-231 cells are the most aggressive and rapidly form metastatic tumors in xenograft transplant models, and exhibited very high proliferation rates when I plated them as three-dimensional cultures in Matrigel. Quantitative image analysis of microtubules in six breast cancer cell lines (MDA-MB-231, LY2, ZR75B, HCC-1143, HCC-1428, HCC-3153) demonstrated that the rotational spindle rocking of MDA-MB-231 cells during metaphase appears coupled with a significant increase in microtubule polymerization rates during interphase, which likely shortens interphase and accelerates cell cycle progression and mitotic entry. Unlike the uniform treadmilling rates in kinetochore microtubules during metaphase I measured across cell lines, the alterations in interphase microtubule dynamics together with the abnormal mitotic spindle oscillations may represent a therapeutically targetable disrupted mechanism of spindle positioning in receptor triple-negative breast cancer cells leading to tumor aggressiveness. See:
github.com/amatov/InstantaneousFlowTracker, github.com/amatov/ClusterTrackTubuline,
github.com/amatov/DyneinFunctionAnalysis,
github.com/amatov/SegmentationBiomarkerCTC,
github.com/amatov/AutomatedBlotQuantification, github.com/amatov/DataSetTracker
... It is required for cilia formation in neuronal cells in vitro and is crucial for cilia length control, cilia disassembly, cell cycle reentry, neural stem cell maintenance and microtubule regulation [35][36][37][38][39][40]. In addition to this well-studied centrosomal role, a role in neuronal migration has been described, downstream of the neurogenic transcription factor Ascl1/Mash1 [41]. Indeed, knockdown of Cpap in mouse produces a neuronal migration phenotype reminiscent of Dyx1c1 and Dcdc2 knockdown phenotypes in rats [3,6,41]. ...
... In addition to this well-studied centrosomal role, a role in neuronal migration has been described, downstream of the neurogenic transcription factor Ascl1/Mash1 [41]. Indeed, knockdown of Cpap in mouse produces a neuronal migration phenotype reminiscent of Dyx1c1 and Dcdc2 knockdown phenotypes in rats [3,6,41]. ...
... Both Dyx1c1 and Dcdc2 have been shown to produce neuronal migration defects when knocked down in rats [3,6]. Similarly, CPAP has been shown to regulate neuronal migration independently of its function at the centrosome, via its microtubule-destabilizing domain PN2-3 [41]. CPAP controls, via its PN2-3 domain, ciliary length and centriolar and ciliary tubulin assembly and disassembly [39,[56][57][58]. ...
Background
DYX1C1 (DNAAF4) and DCDC2 are two of the most replicated dyslexia candidate genes in genetic studies. They both have demonstrated roles in neuronal migration, in cilia growth and function and they both are cytoskeletal interactors. In addition, they both have been characterized as ciliopathy genes. However, their exact molecular functions are still incompletely described. Based on these known roles, we asked whether DYX1C1 and DCDC2 interact on the genetic and the protein level.
Results
Here, we report the physical protein-protein interaction of DYX1C1 and DCDC2 as well as their respective interactions with the centrosomal protein CPAP (CENPJ) on exogenous and endogenous levels in different cell models including brain organoids. In addition, we show a synergistic genetic interaction between dyx1c1 and dcdc2b in zebrafish exacerbating the ciliary phenotype. Finally, we show a mutual effect on transcriptional regulation among DYX1C1 and DCDC2 in a cellular model.
Conclusions
In summary, we describe the physical and functional interaction between the two genes DYX1C1 and DCDC2. These results contribute to the growing understanding of the molecular roles of DYX1C1 and DCDC2 and set the stage for future functional studies.
... Defects in neuroblast migration, an important step during in vivo cortical neurogenesis in mice, have been reported to contribute to cortical malformations, including microcephaly. 42,43 T. gondii infection has also shown the capacity to recruit microtubules to the vicinity of its parasitophorous vacuole. 44e46 Cytoskeleton proteins such as tubulin have been reported to play a major role in neuroblast migration and cortical neurogenesis, 47,48 thus indicating that infected progenitor cells may indeed display migratory defects. ...
Congenital toxoplasmosis constitutes a major cause of pre- and post-natal complications. Fetal infection with Toxoplasma gondii influences development and can lead to microcephaly, encephalitis, and neurological abnormalities. To date, no systematic study concerning the effect of neural progenitor cell infection by T. gondii is available. We infected cortical intermediate progenitor cell cultivated as neurospheres obtained from E16.5 Swiss Webster mice with T. gondii (Me49 strain) tachyzoites to mimic the developing mouse cerebral cortex in vitro. Infection decreased cell proliferation as detected by Ki67 staining at 48 and 72 hours post infection (hpi) in floating neurospheres, resulting in reduced cellularity at 96 hpi. Neurogenesis-related transcription factors Tbr1, Math1 and Hes1 had transient expression decrease in infected cultures, while Sox2 protein levels remained unaltered. Neurogenic potential, assessed in plated neurospheres, was impaired in infected cultures, as indicated by decreased late neuronal marker, neurofilament heavy chain (NF-200) immunoreactivity. Infected cultures exhibited decreased overall migration rates, at 48 and 120 h after plating. These findings indicate that T. gondii infection of neural progenitor cells may lead to reduced neurogenesis due to an imbalance in cell proliferation alongside an altered migratory profile. If translated to the in vivo situation, these data could explain, in part, the cortical malformations observed in congenitally infected individuals.
... Optimal microtubule dynamics are necessary for the translocation of the nucleus (Garcez et al., 2015;Marín et al., 2010). Hence, we cultured MGE explants from Rac1/3dmut and control embryos and labeled the microtubule cage surrounding the nucleus for tyrosinated tubulin (ty-tubulin) as well as the stable microtubules for acetylated tubulin (ac-tubulin) in migrating interneurons 48 h after plating (Fig. S1H). ...
... We previously observed a reduction in ac-tubulin in Rac1/3dmut CINs (Tivodar et al., 2015). These observations are in agreement with other reports showing that instability of microtubules (as well as excessive stability) affects nuclear translocation and the distance of the centrosome from the nucleus (Garcez et al., 2015;Tanaka et al., 2004;Valiente and Marín, 2010). MGE-derived interneurons treated with nocodazole, which destabilizes microtubules, exhibit shortened leading processes and decreased migration speed (Baudoin et al., 2007). ...
Rho GTPases, among them Rac1 and Rac3, are major transducers of extracellular signals and are involved in multiple cellular processes. In cortical interneurons, the neurons that control excitation/inhibition balance of cortical circuits, Rac1 and Rac3 are essential for their development. Ablation of both, leads to a severe reduction in the numbers of mature interneurons found in the murine cortex, which is partially due to abnormal cell cycle progression of interneuron precursors and defective formation of growth cones in young neurons. Here we present new evidence that upon Rac1 and Rac3 ablation, centrosome, Golgi complex and lysosome positioning are significantly perturbed, thus affecting both interneuron migration and axon growth. Moreover, for the first time we provide evidence of altered expression and localization of the two-pore channel 2 (TPC2) voltage-gated ion channel that mediates Ca2+ release. Pharmacological inhibition of TPC2 negatively affected axonal growth and migration of interneurons. Our data taken together suggest that TPC2 contributes to the severe phenotype in axon growth initiation, extension and interneuron migration in the absence of Rac1 and Rac3.
... It is required for cilia formation in neuronal cells in vitro and is crucial for cilia length control, cilia disassembly, cell cycle reentry, neural stem cell maintenance and microtubule regulation (35)(36)(37)(38)(39). In addition to this well-studied centrosomal role, a role in neuronal migration has been described, downstream of the neurogenic transcription factor Ascl1/Mash1 (40). ...
... Indeed, knockdown of Cpap in mouse produces a neuronal migration phenotype reminiscent of Dyx1c1 and Dcdc2 knockdown phenotypes in rats (3,6,40). ...
... Both Dyx1c1 and Dcdc2 have been shown to produce neuronal migration defects when knocked down in rats (3,6). Similarly, CPAP has been shown to regulate neuronal migration independently of its function in centrosome, via its microtubule-destabilizing domain PN2-3 (40). CPAP controls, via its PN2-3 domain, ciliary length and centriolar and ciliary tubulin assembly and disassembly (39,(59)(60)(61). ...
Background: DYX1C1 (DNAAF4) and DCDC2 are two of the most replicated dyslexia candidate genes in genetic studies. They both have demonstrated roles in neuronal migration, in cilia growth and function and they both are cytoskeletal interactors. In addition, they both have been characterized as ciliopathy genes. However, their exact molecular functions are still incompletely described. Based on these known roles, we asked whether DYX1C1 and DCDC2 interact on the genetic and the protein level.
Results:Here, we report the physical protein-protein interaction of DYX1C1 and DCDC2 via the centrosomal protein CPAP (CENPJ) on exogenous and endogenous levels in different cell models including brain organoids. In addition, we show a synergistic genetic interaction between dyx1c1and dcdc2b in zebrafish exacerbating the ciliary phenotype and suggesting a common pathway in development. Finally, we show a mutual effect on transcriptional regulation among DYX1C1 and DCDC2 in a cellular model.
Conclusions: In summary, we describe the physical and functional interaction between the two genes DYX1C1 and DCDC2 that link them to a common pathway. These results contribute to the growing understanding of the molecular roles of DYX1C1 and DCDC2 and set the stage for future functional studies.
... These results are in line with the fact that ZIKV and other flaviviruses are known to replicate in the ER [71]; however, the specifics regarding viral assembly within the ER remain elusive [72]. On the other hand, the centrosome assembly disturbances, in addition to other proteins, have been known to contribute to significant developmental defects in genetic microcephaly [25,73], or caused by ZIKV [44]. Altering division plane in progenitor cells, core centrosomal proteins, such as CEP128, are upregulated in Br ZIKV-infected neurospheres (Supplementary Table 2). ...
Brain abnormalities and congenital malformations have been linked to the circulating strain of Zika virus (ZIKV) in Brazil since 2016 during the microcephaly outbreak; however, the molecular mechanisms behind several of these alterations and differential viral molecular targets have not been fully elucidated. Here we explore the proteomic alterations induced by ZIKV by comparing the Brazilian (Br ZIKV) and the African (MR766) viral strains, in addition to comparing them to the molecular responses to the Dengue virus type 2 (DENV). Neural stem cells (NSCs) derived from induced pluripotent stem (iPSCs) were cultured both as monolayers and in suspension (resulting in neurospheres), which were then infected with ZIKV (Br ZIKV or ZIKV MR766) or DENV to assess alterations within neural cells. Large-scale proteomic analyses allowed the comparison not only between viral strains but also regarding the two- and three-dimensional cellular models of neural cells derived from iPSCs, and the effects on their interaction. Altered pathways and biological processes were observed related to cell death, cell cycle dysregulation, and neurogenesis. These results reinforce already published data and provide further information regarding the biological alterations induced by ZIKV and DENV in neural cells.
... Moreover, in the developing brain, Cenpj is expressed in proliferative zones and in the cortical plate, where postmitotic neurons migrate to. In vivo, acute loss-of-function of this gene not only results in proliferation abnormalities but also in neuronal migration and morphology defects (Garcez et al., 2015). ...
... The size of the samples was based on previously published study (Garcez et al., 2015) and we performed a post-hoc power analysis for 80% power(https://clinc alc.com/stats/ Power.aspx). ...
... Previous work done by our group has shown that CENPJ can regulate the migration of post-mitotic cortical neurons (Garcez et al., 2015). ...
Glioblastoma is the most common and malignant type of primary brain tumor. Previous studies have shown that alterations in centrosome amplification and its components are frequently found in treatment‐resistant tumors and may be associated with tumor progression. A centrosome protein essential for centrosome biogenesis is the centromere protein J (CENPJ), known to control the proliferation of neural progenitors and hepatocarcinoma cells, and also neuronal migration. However, it remains unknown the role of CENPJ in glioblastoma. Here we show that CENPJ is overexpressed in human glioblastoma cell lines in comparison to human astrocytes. Using bioinformatics analysis, we find that high Cenpj expression is associated with poor prognosis in glioma patients. Examining Cenpj loss of function in glioblastoma by siRNA transfection, we find impairments in cell proliferation and migration. Using a Cenpj mutant version with the deleted PN2‐3 or TCP domain, we found that a conserved PN2‐3 region is required for glioblastoma migration. Moreover, Cenpj downregulation modulates glioblastoma morphology resulting in microtubules stabilization and actin filaments depolymerization. Altogether, our findings indicate that CENPJ controls relevant aspects of glioblastoma progression and might be a target for therapeutic intervention and a biomarker for glioma malignancy. image
... The cleavage plane orientation is determined by the orientation of the mitotic spindle. It is therefore not surprising that a premature neuronal differentiation and cortical disorders such as lissencephaly or microcephaly are associated with mutations in genes that have a role in mitotic spindle orientation or mitotic spindle organization (Feng and Walsh, 2004;Fish et al., 2006;Gauthier-Fisher et al., 2009;Garcez et al., 2015). ...
During development, the decision of stem and progenitor cells to switch from proliferation to differentiation is of critical importance for the overall size of an organ. Too early a switch will deplete the stem/progenitor cell pool, and too late a switch will not generate the required differentiated cell types. With a focus on the developing neocortex, a six-layered structure constituting the major part of the cerebral cortex in mammals, we discuss here the cell biological features that are crucial to ensure the appropriate proliferation vs. differentiation decision in the neural progenitor cells. In the last two decades, the neural progenitor cells giving rise to the diverse types of neurons that function in the neocortex have been intensely investigated for their role in cortical expansion and gyrification. In this review, we will first describe these different progenitor types and their diversity. We will then review the various cell biological features associated with the cell fate decisions of these progenitor cells, with emphasis on the role of the radial processes emanating from these progenitor cells. We will also discuss the species-specific differences in these cell biological features that have allowed for the evolutionary expansion of the neocortex in humans. Finally, we will discuss the emerging role of cell cycle parameters in neocortical expansion.
