Single-cell delineation of lineage and genetic identity in the mouse brain

During neurogenesis, mitotic progenitor cells lining the ventricles ofthe embryonic mouse brain undergo their final rounds of cell division, giving rise to a wide spectrum of postmitotic neurons and glia(1,2). The link between developmental lineage and cell-type diversity remains an open question. Here we used massively parallel tagging of progenitors to track clonal relationships and transcriptomic signatures during mouse forebrain development. We quantified clonal divergence and convergence across all major cell classes postnatally, and found diverse types of GABAergic neuron that share a common lineage. Divergence of GABAergic clones occurred during embryogenesis upon cell-cycle exit, suggesting that differentiation into subtypes is initiated as a lineage-dependent process at the progenitor cell level

The extracellular matrix molecule hyaluronic acid regulates hippocampal synaptic plasticity by modulating postsynaptic L-type Ca(2+) channels.

Although the extracellular matrix plays an important role in regulating use-dependent synaptic plasticity, the underlying molecular mechanisms are poorly understood. Here we examined the synaptic function of hyaluronic acid (HA), a major component of the extracellular matrix. Enzymatic removal of HA with hyaluronidase reduced nifedipine-sensitive whole- cell Ca2+ currents, decreased Ca2+ transients medi- ated by L-type voltage-dependent Ca2+ channels (L-VDCCs) in postsynaptic dendritic shafts and spines, and abolished an L-VDCC-dependent compo- nent of long-term potentiation (LTP) at the CA3-CA1 synapses in the hippocampus. Adding exogenous HA, either by bath perfusion or via local delivery near recorded synapses, completely rescued this LTP component. In a heterologous expression system, exogenous HA rapidly increased currents mediated by Cav1.2, but not Cav1.3, subunit-containing L- VDCCs, whereas intrahippocampal injection of hyal- uronidase impaired contextual fear conditioning. Our observations unveil a previously unrecognized mech- anism by which the perisynaptic extracellular matrix influences use-dependent synaptic plasticity through regulation of dendritic Ca2+ channels

The extracellular matrix component hyaluronic acid supports hippocampal synaptic plasticity by modulating postsynaptic L-type Ca2+ channels.

Although the extracellular matrix plays an important role in regulating use-dependent synaptic plasticity, the underlying molecular mechanisms are poorly understood. Here, we examined the synaptic function of hyaluronic acid (HA), a major element of the extracellular matrix. Enzymatic removal of HA with hyaluronidase reduced nifedipine-sensitive whole-cell Ca2+ currents and Ca2+ transients mediated by L-type voltage-dependent Ca2+ channels (L-VDCCs) in individual dendritic shafts and spines of CA1 pyramidal cells, and abolished an L-VDCC-dependent component of long-term potentiation (LTP) at the CA3-CA1 synapses. Adding exogenous HA, either by bath perfusion or via local delivery near to recorded synapses, completely rescued this LTP component. In a heterologous expression system, HA increased currents mediated by Cav1.2 but not Cav1.3 subunit-containing L-VDCCs. Injection of hyaluronidase in the brain impaired contextual fear conditioning. Our observations unveil a previously unrecognized mechanism by which the perisynaptic HA-rich extracellular matrix influences use-dependent synaptic plasticity through regulation of dendritic Ca2+ channels

Direct generation of functional dopaminergic neurons from mouse and human fibroblasts

Transplantation of dopaminergic neurons can potentially improve the clinical outcome of Parkinson's disease, a neurological disorder resulting from degeneration of mesencephalic dopaminergic neurons. In particular, transplantation of embryonic-stem-cell-derived dopaminergic neurons has been shown to be efficient in restoring motor symptoms in conditions of dopamine deficiency. However, the use of pluripotent-derived cells might lead to the development of tumours if not properly controlled. Here we identified a minimal set of three transcription factors--Mash1 (also known as Ascl1), Nurr1 (also known as Nr4a2) and Lmx1a--that are able to generate directly functional dopaminergic neurons from mouse and human fibroblasts without reverting to a progenitor cell stage. Induced dopaminergic (iDA) cells release dopamine and show spontaneous electrical activity organized in regular spikes consistent with the pacemaker activity featured by brain dopaminergic neurons. The three factors were able to elicit dopaminergic neuronal conversion in prenatal and adult fibroblasts from healthy donors and Parkinson's disease patients. Direct generation of iDA cells from somatic cells might have significant implications for understanding critical processes for neuronal development, in vitro disease modelling and cell replacement therapies