Mechanisms of Cell Fate Decision

Understanding the human brain is one of the most exciting challenges in science. One defining characteristic of the brain is the remarkable structural and functional complexity of the neural architecture. To reveal the principles underlying the architecture, one productive strategy is to study the design principles of the neural circuitry by observing their origin during embryonic development (see http://8e.devbio.com/article.php?id=145). Our research focuses on the elaborate genetic pathways that generate neural diversity, connectivity and ultimately the functional architecture of the brain.

Stem cells

Directed differentiation of neural progenitor cells to GFAP+ astrocytes or Map-2+ neurons in vivo

A major theme in our group is the study of stem cells as the cellular substrate for development. Stem cells are genetically malleable precursor cells. During tissue formation and organogenesis the intrinsic differentiation capacities of stem cells are shaped by their interactions with the cellular and molecular environment. It is now well established that neural stem cells are not confined to embryonic stages but persist into adulthood. Stem cell function in the adult context is under intense investigation, as is the question of whether the innate developmental plasticity of stem cells can be harnessed to improve regeneration of the nervous system after disease or injury.

microRNA and stem cell biology

mLin-41 in postimplantation embryo

Postimplantation embryo

mLin-41 in fallopian tubes and uterus

Fallopian tubes and uterus

Seminiferous tubules

Seminiferous tubules

Our interests can be summed up in two broad questions: 1) What makes a stem cell a stem cell, and 2) How do the properties of a differentiating stem cell change with time? Our working hypothesis is that these fundamental properties of the cell may be determined in part by a large, recently discovered class of regulatory RNA genes termed microRNA.

What do microRNA do?

Localization of miRNA pathway protein Ago1 in dendritic arbors of hippocampal neurons

Localization of miRNA pathway protein Ago1 in dendritic arbors of hippocampal neurons

microRNAs are recently discovered RNA effectors that transcend the traditional “one gene, one protein” hypothesis. microRNA consist of nothing more than discreet, ~22 nt RNA sequences frequently expressed from intergenic regions of the chromosome and from introns. microRNA appear to participate in genetic regulation at three levels: 1) by selectively deactivating mRNAs, particularly those encoding developmental regulators, 2) by influencing the relative accessibility of defined regions of chromatin and thus transcriptional control, and 3) by directly binding to proteins and altering their activity. Hundreds of microRNA genes have been identified in mammalian cells, expression studies have demonstrated both tissue and temporal specificity in individual microRNA expression.

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Control electroporation

Control electroporation

Let-7 sensor electroporation

Let-7 sensor electroporation

NLS-tagged dsRed encoded by the sensor mRNA is repressed in response to the let-7 miRNA. A co-transfected MS2-eGFP reporter binds the sensor mRNA.

There is now strong evidence for microRNA involvement in the regulation of developmental timing PM:12142272, growth control PM:16009126, apoptosis PM:15372042, and cell fate choice PM:16311325. Specifically in the brain, microRNA participate in the establishment of cellular identity PM:14685240, connectivity PM:16421561, and the translational control of memory formation PM:16413491.

There are any number of great review articles discussing microRNAs in general and their functions in the nervous system in particular. See, for example, a recent introductory treatment from our group (Wulczyn, Pekarik and Smirnova., Enzyclopedia of Neuroscience, Springer Verlag 2008).

 

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Research database

For more details please use the Charité Öffnet externen Link im aktuellen Fensterresearch database