Transcription factor has key role in development of cortical interneurons

08 November 2012

NIMR scientists have shown that the genome organizer SATB1 has a key role in the development of cortical interneurons. The research is published in Cell Reports.

Motor planning, sensory representation and cognition depend on the assembly of highly complex neural circuits in the mammalian cortex. These circuits are made up of two major neuronal subtypes: the principal excitatory pyramidal neurons and the cortical interneurons. This latter group of neurons, albeit relatively small in number, provide the major inhibitory input to cerebral circuits and are absolutely critical for balanced cerebral function. Cortical inhibitory neurons are generated in the ventral forebrain during embryogenesis and arrive into the cortex as immature precursors. Within the cortex they go through a lengthy process of terminal differentiation and maturation in order to acquire all the morphological and physiological characteristics that are required for their functional integration into cerebral circuits. The molecular and signalling cascades that regulate the developmental of cortical interneurons within cortical circuits have been unclear.

Myrto Denaxa and her colleagues in Vassilis Pachnis’ lab in the Division of Molecular Neurobiology have been exploring the mechanisms that underlie the formation of inhibitory networks in the mouse brain. Their recent work demonstrates that the transcription factor and chromatin organizer SATB1 has a key role in driving the terminal differentiation and maturation of a major subpopulation of cortical interneurons. Using a series of in vivo and in vitro studies they have demonstrated that SATB1 coordinately controls the expression of multiple subtype-specific and interneuron-wide genes, in a manner that defines their mature functional state. This work also provides evidence that expression of the Satb1 gene is induced by neuronal activity (see figure), thus providing a mechanistic understanding as to how spontaneous activity in the immature brain drives neuronal maturation.

Taken together, these studies indicate that SATB1 is a molecular hub that co-ordinates extrinsic signals and intrinsic genetic programs that allow immature cortical interneurons to acquire subtype-defining properties, which then allow them to integrate functionally into cortical neuronal circuits. It is likely that such molecular hubs are likely to be present in many different parts of the central and peripheral nervous system.

Vassilis Pachnis

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Cultures of cortical interneurons (green) maintained under conditions that promote neuronal activity. Many of these neurons express the transcription factor SATB1 (red).

Original article

Myrto Denaxa, Melanie Kalaitzidou, Anna Garefalaki, Angeliki Achimastou, Reena Lasrado, Tamara Maes, Vassilis Pachnis. (2012)

Maturation-promoting activity of Satb1 in MGE-derived cortical interneurons

Cell Reports Epub ahead of print. Publisher abstract

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