Interneuron development - molecular diversity - phenotypic convergence - gene regulatory networks - behavior - evolution
CNS comprises remarkable cellular diversity. The most prominent cell types in the CNS are excitatory (glutamatergic) and inhibitory (GABA- and glycinergic) projection- and interneurons.
The interneuron subclass can be further divided into a wide range of subtypes, depending on their molecular profiles, function, location and neuronal network contributions.
In recent years, single-cell genomics approaches have opened new possibilities for in-detail understanding of the building blocks of complex biological systems such as the CNS. In our lab, we are using single-cell RNA-sequencing in order to profile the cell type diversity in developing vertebrate (mouse) ventral brain.
How are cell fates specified during development?
Terminal differentiation of neurons is thought to be initiated and regulated by terminal selector transcription factors at the time of the cell cycle exit. In the developing interneurons, different sets of terminal differentiation factors are used, depending of the developmental origin of the neuronal precursors. For example, while the Gad1 and Gad2 gene expression is initiated by DLX transcription factors in the forebrain GABAergic interneurons, the same genes are activated by GATA and TAL transcription factors in thedeveloping thalamus and midbrain, and by PTF1a in the cerebellum.
The variation of the regulatory events leading to the expression of functionally similar gene sets in related cell types is analogous to phenotypic convergence in species. We are interested in the molecular mechanisms of this process in the level of cell type diversification.
[Figure modified from Achim et al, 2013, Cell Mol Life Sci]
Which regulatory events control the differentiation of interneurons?
We are using mouse transgenesis for labelling of specific cell types and inactivating key developmental regulators, in combination with RNA-seq, open chromatin mapping, and ChIP-seq in order to understand the:
- activation of terminal differentiation genes at the onset of interneuron differentiation
- onset of selector gene expression
- variation of regulatory landscapes responsive to selector genes across functionally similar cell types
Ventral brain areas, namely the hypothalamus, ventral midbrain and brainstem reticular formation comprise a collection of nuclei that are central the regulation of motivational state and execution of reward behaviors.
The brainstem nuclei are also involved in the control of emotional states like arousal, attention, fear.
Thirdly, several innate and instinctive behaviors are tied to this brain region, such as reproductive cycles, circadian rhythms, hunger and thirst.
We are interested in linking specific, molecularly defined cell types to the behavioral aspects they regulate, using genetics models and behavioral assays in mouse, and correlative genome analyses and disease population screening in human.