University of California

John L Rubenstein

Arturo Alvarez-Buylla

Arnold Kriegstein

Cory R Nicholas

Scott C Baraban

Michael S German

Dennis J Hartigan-O'Connor

Lori Sussel

Thorsten Stuehmer

Kyuson Yun

Roger A Pedersen

Stewart Anderson

Maike Sander

Juanito J Meneses

Marina Mione

Arnold R Kriegstein

Methods and systems for generating MGE precursor cells in vitro as well as compositions of enriched MGE precursor cells are provided. The methods and systems provide efficient production of MGE precursors. The methods and systems disclosed herein provide functional MGE precursors which differentiate into functional GABAergic interneurons.

In vitro production of medial ganglionic eminence precursor cells

Restoration or increase of inhibitory interneuron function in vivo is achieved by transplantation of MGE cells into the brain. Compositions containing MGE cells are provided as are uses to treat various diseases characterized by abnormal inhibitory interneuron function or in cases where increase inhibition may ameliorate neural circuits that are abnormally activated.

Transplantation of neural cells

Restoration or increase of inhibitory interneuron function in vivo is achieved by transplantation of MGE cells into the brain. Compositions containing MGE cells are provided as are uses to treat various diseases characterised by abnormal inhibitory interneuron function or in cases where increase inhibition may ameliorate neural circuits that are abnormally activated.

The invention features methods and compositions for the production of GABAergic cells, particularly GABAergic neurons. Production of GABAergic cells is accomplished by increasing activity of a Dlx gene (e.g., DLX1, DLX2, or DLX5) in an immature neuronal cell. The increase in Dlx activity causes differentiation of the immature neuronal cell into a neuronal cell exhibiting the GABAergic phenotype. The invention also encompasses use of GABAergic cells produced by the method of the invention in, for example, identification of agents that affect GABAergic cell activity and survival, and in replacement therapy.

Production of gabaergic cells

The present invention features mouse models for Nkx-2.2 gene function and for Nkx-6.1 gene function, wherein the transgenic mouse is characterized by having a defect in Nkx-2.2 gene function or a defect in Nkx-6.1 gene function (where, because Nkx-2.2 acts upstream of Nkx-6.1, a defect in Nkx-2.2 gene function affects Nkx-6.1 gene function) and by having a decreased number of insulin-producing cells relative to a normal mouse. Where the transgenic mouse contains a defect in Nkx-2.2 gene function, the mouse is further characterized by a decreased number of serotonin-producing cells relative to a normal mouse. The transgenic mice may be either homozygous or heterozygous for the Nkx-2.2 or Nkx-6.1 defect.

NKX-2.2 and NKX-6.1 transgenic mouse models for diabetes, depression,

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San Francisco, CA, United States of America

John L Rubenstein