Project description:The connectivity, activity, and plasticity of the telencephalon are shaped by pallial and subpallial GABAergic neurons, two large populations that are produced in the embryonic medial, caudal and lateral ganglionic eminences in a highly complicated manner. Dysregulated development of GABAergic neurons is associated with neuropsychiatric disorders. However, knowledge about the specification of GABAergic neuron subtypes is limited. Here, using single-cell RNA sequencing combined with loss-of-function we delineated developmental trajectories and revealed transcriptional programs that specify GABAergic neuron subtypes in each GE lineage and transcription factors that direct lineage bifurcation decisions. Our study illuminates the control of production between pallial and subpallial populations and offers transcriptomic insights into the pathogenesis of GABAergic neuron-related disorders.
Project description:The connectivity, activity, and plasticity of the telencephalon are shaped by pallial and subpallial GABAergic neurons, two large populations that are produced in the embryonic medial, caudal and lateral ganglionic eminences in a highly complicated manner. Dysregulated development of GABAergic neurons is associated with neuropsychiatric disorders. However, knowledge about the specification of GABAergic neuron subtypes is limited. Here, using single-cell RNA sequencing combined with loss-of-function we delineated developmental trajectories and revealed transcriptional programs that specify GABAergic neuron subtypes in each GE lineage and transcription factors that direct lineage bifurcation decisions. Our study illuminates the control of production between pallial and subpallial populations and offers transcriptomic insights into the pathogenesis of GABAergic neuron-related disorders.
Project description:The connectivity, activity, and plasticity of the telencephalon are shaped by pallial and subpallial GABAergic neurons, two large populations that are produced in the embryonic medial, caudal and lateral ganglionic eminences in a highly complicated manner. Dysregulated development of GABAergic neurons is associated with neuropsychiatric disorders. However, knowledge about the specification of GABAergic neuron subtypes is limited. Here, using single-cell RNA sequencing combined with loss-of-function we delineated developmental trajectories and revealed transcriptional programs that specify GABAergic neuron subtypes in each GE lineage and transcription factors that direct lineage bifurcation decisions. Our study illuminates the control of production between pallial and subpallial populations and offers transcriptomic insights into the pathogenesis of GABAergic neuron-related disorders.
Project description:Despite recent advances in the identification of lymphoid-restricted progenitors, the transcription factors essential for their generation remain to be identified. Here we describe an unexpected role for the myeloid oncogene Mef2c in multipotent progenitors (MPPs), where it is required for pan-lymphoid differentiation. Mef2c deficiency was associated with profound defects in B, T, NK cell and common lymphoid progenitor production and an enhanced myeloid output. Mef2c deficiency in MPPs leads to downregulation of several key lymphoid regulators and the upregulation of the myeloid factor C/EBPa. Our studies also show that Mef2c is a critical transcriptional target of PU.1 during lymphopoiesis. Thus, Mef2c is a crucial component of the transcriptional network that regulates lymphoid specification and cell fate choice in MPPs.
Project description:Antigen encounter directs CD4+ T cells to differentiate into T-helper or -regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern -helper versus -regulatory fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4+ T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells developed enhanced Th2 and Th9 inflammation and pathophysiological features of atopic asthma upon allergen exposure. Following T cell activation, Cul5 formed a complex with CIS and pJak1. Loss of Cul5 function resulted in reduced ubiquitylation and increased stability of pJak1, elevated STAT6 activity, and a reduced threshold for IL-4 receptor signaling. In keeping with this, Cul5-deficient T cells deviated from Treg to Th9 differentiation in low IL-4 conditions. These data support that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma.
Project description:The ventricular-subventricular zone (V-SVZ) is the largest neurogenic region of the postnatal forebrain, containing neural stem cells (NSCs) that emerge from both the embryonic pallium and subpallium. Despite of this dual origin, glutamatergic neurogenesis declines rapidly after birth, while gabaergic neurogenesis persists throughout life. We performed single-cell RNA-sequencing (scRNA-Seq) of the postnatal dorsal V-SVZ for unravelling the mechanisms leading to pallial lineage germinal activity silencing. We show that pallial NSCs enter a state of deep quiescence, characterized by high BMP-signaling, reduced transcriptional activity and Hopx expression, whilst in contrast, subpallial NSCs remain primed for activation. Induction of deep quiescence is paralleled by a rapid blockade of glutamatergic neurons production and differentiation. Finally, manipulation of Bmpr1a demonstrates its key role in mediating these effects. Together, our results highlight a central role of BMP-signaling in synchronizing quiescence induction and blockade of neuronal differentiation to rapidly silence pallial germinal activity after birth.