Key Publications

Temporal and sequential transcriptional dynamics define lineage shifts in corticogenesis

Tanzila Mukhtar, Jeremie Breda, Manal A Adam, Marcelo Boareto, Pascal Grobecker, Zahra Karimaddini, Alice Grison, Katja Eschbach, Ramakrishnan Chandrasekhar, Swen Vermeul, Michal Okoniewski, Mikhail Pachkov, Corey C Harwell, Suzana Atanasoski, Christian Beisel, Dagmar Iber, Erik van Nimwegen, Verdon Taylor

November 8, 2022

The cerebral cortex contains billions of neurons, and their disorganization or misspecification leads to neurodevelopmental disorders. Understanding how the plethora of projection neuron subtypes are generated by cortical neural stem cells (NSCs) is a major challenge. Here, we focused on elucidating the transcriptional landscape of murine embryonic NSCs, basal progenitors (BPs), and newborn neurons (NBNs) throughout cortical development. We uncover dynamic shifts in transcriptional space over time and heterogeneity within each progenitor population. We identified signature hallmarks of NSC, BP, and NBN clusters and predict active transcriptional nodes and networks that contribute to neural fate specification. We find that the expression of receptors, ligands, and downstream pathway components is highly dynamic over time and throughout the lineage implying differential responsiveness to signals. Thus, we provide an expansive compendium of gene expression during cortical development that will be an invaluable resource for studying neural developmental processes and neurodevelopmental disorders.

Genetic Inactivation of Notch1 Synergizes with Loss of Trp53 to Induce Tumor Formation in the Adult Mouse Forebrain

Elena Parmigiani, Claudio Giachino

November 2, 2022

Simultaneous genetic inactivation of the key Notch signaling mediator RBP-Jk and p53 leads to the formation of forebrain tumors in mice, suggesting a tumor suppressor role of the Notch pathway in this context. However, the contribution of individual Notch receptors to the tumor-suppressive activity of Notch signaling in the brain remains elusive. Here, we show that simultaneous Notch1 and Notch2 deletion, similar to complete ablation of canonical Notch signaling by Rbpj inactivation, cooperates with Trp53 deletion to promote tumor growth in the adult forebrain. We also demonstrate that inactivation of Notch1 and Trp53 in cells with active Notch signaling is sufficient to induce brain tumor or hyperplasia formation. Analysis of tumor location suggests a multifocal origin and shows that ventral forebrain regions and olfactory bulbs are the most affected sites. Hence, Notch1 cooperates with p53 to repress malignant transformation in the adult mouse forebrain.

Interferon-γ resistance and immune evasion in glioma develop via Notch-regulated co-evolution of malignant and immune cells

Elena Parmigiani, Robert Ivanek, Chiara Rolando, ..., Roxane Tussiwand, Verdon Taylor, Claudio Giachino

July 7, 2022

Gliomas are aggressive brain tumors and resistant to current standard and targeted therapeutic interventions. Immune evasion is pronounced in glioma, but the underlying mechanisms remain poorly understood. Parmigiani et al. demonstrate that suppression of Notch signaling enables glioma cells to evade immune surveillance and increases aggressiveness. The findings of the study provide insights into how brain tumor cells shape their microenvironment to evade control by the immune system.

Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma

Parmigiani, E. Giachino, C. Taylor, V.

October 15, 2020

Although the role of NOTCH signaling has been extensively studied in health and disease, many questions still remain unresolved. Being crucial for tissue homeostasis, NOTCH signaling is also implicated in multiple cancers by either promoting or suppressing tumor development. In this review we illustrate the context-dependent role of NOTCH signaling during tumorigenesis with a particular focus on gliomas, the most frequent and aggressive brain tumors in adults. For a long time, NOTCH has been considered an oncogene in glioma mainly by virtue of its neural stem cell-promoting activity. However, the recent identification of NOTCH-inactivating mutations in some glioma patients has challenged this notion, prompting a re-examination of the function of NOTCH in brain tumor subtypes. We discuss recent findings that might help to reconcile the controversial role of NOTCH signaling in this disease, and pose outstanding questions that still remain to be addressed.

Tead transcription factors differentially regulate cortical development

Mukhtar, T. Breda, J. Grison, A. Karimaddini, Z. Grobecker, P. Iber, D. Beisel, C. van Nimwegen E. & Taylor, V.

March 13, 2020

Neural stem cells (NSCs) generate neurons of the cerebral cortex with distinct morphologies and functions. How specific neuron production, differentiation and migration are orchestrated is unclear. Hippo signaling regulates gene expression through Tead transcription factors (TFs). We show that Hippo transcriptional coactivators Yap1/Taz and the Teads have distinct functions during cortical development. Yap1/Taz promote NSC maintenance and Satb2+ neuron production at the expense of Tbr1+ neuron generation. However, Teads have moderate effects on NSC maintenance and do not affect Satb2+ neuron differentiation. Conversely, whereas Tead2 blocks Tbr1+ neuron formation, Tead1 and Tead3 promote this early fate. In addition, we found that Hippo effectors regulate neuronal migration to the cortical plate (CP) in a reciprocal fashion, that ApoE, Dab2 and Cyr61 are Tead targets, and these contribute to neuronal fate determination and migration. Our results indicate that multifaceted Hippo signaling is pivotal in different aspects of cortical development.

Id4 Downstream of Notch2 Maintains Neural Stem Cell Quiescence in the Adult Hippocampus

Zhang, R. Boareto, M. Engler, A. Louvi, A. Giachino, C. Iber, D. & Taylor, V.

Aug 6, 2019

Neural stem cells (NSCs) in the adult mouse hippocampal dentate gyrus (DG) are mostly quiescent, and only a few are in cell cycle at any point in time. DG NSCs become increasingly dormant with age and enter mitosis less frequently, which impinges on neurogenesis. How NSC inactivity is maintained is largely unknown. Here, we found that Id4 is a downstream target of Notch2 signaling and maintains DG NSC quiescence by blocking cell-cycle entry. Id4 expression is sufficient to promote DG NSC quiescence and Id4 knockdown rescues Notch2-induced inhibition of NSC proliferation. Id4 deletion activates NSC proliferation in the DG without evoking neuron generation, and overexpression increases NSC maintenance while promoting astrogliogenesis at the expense of neurogenesis. Together, our findings indicate that Id4 is a major effector of Notch2 signaling in NSCs and a Notch2-Id4 axis promotes NSC quiescence in the adult DG, uncoupling NSC activation from neuronal differentiation.

Notch and Neurogenesis

Engler A, Zhang R, and Taylor V.

Jul 19, 2018

Neurogenesis is the process of forming neurons and is essential during vertebrate development to produce most of the neurons of the adult brain. However, neurogenesis continues throughout life at distinct locations in the vertebrate brain. Neural stem cells (NSCs) are the origin of both embryonic and adult neurogenesis, but their activity and fate are tightly regulated by their local milieu or niche. In this chapter, we will discuss the role of Notch signaling in the control of neurogenesis and regeneration in the embryo and adult. Notch-dependence is a common feature among NSC populations, we will discuss how differences in Notch signaling might contribute to heterogeneity among adult NSCs. Understanding the fate of multiple NSC populations with distinct functions could be important for effective brain regeneration.

TDP-43 induces p53-mediated cell death of cortical progenitors and immature neurons

Vogt MA, Ehsaei Z, Knuckles P, Higginbottom A, Helmbrecht MS, Kunath T, Eggan K, Williams LA, Shaw PJ, Wurst W, Floss T, Huber AB, Taylor V.

May 25, 2018

TAR DNA-binding protein 43 (TDP-43) is a key player in neurodegenerative diseases including frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Accumulation of TDP-43 is associated with neuronal death in the brain. How increased and disease-causing mutant forms of TDP-43 induce cell death remains unclear. Here we addressed the role of TDP-43 during neural development and show that reduced TDP-43 causes defects in neural stem/progenitor cell proliferation but not cell death. However, overexpression of wild type and TDP-43A315T proteins induce p53-dependent apoptosis of neural stem/progenitors and human induced pluripotent cell (iPS)-derived immature cortical neurons. We show that TDP-43 induces expression of the proapoptotic BH3-only genes Bbc3 and Bax, and that p53 inhibition rescues TDP-43 induced cell death of embryonic mouse, and human cortical neurons, including those derived from TDP-43G298S ALS patient iPS cells. Hence, an increase in wild type and mutant TDP-43 induces p53-dependent cell death in neural progenitors developing neurons and this can be rescued. These findings may have important implications for accumulated or mutant TDP-43 induced neurodegenerative diseases.

Verdon Taylor Lab