Forebrain development: From neural plate to cortical specification

The most complicated part of our brain is called the forebrain and forms the cerebral hemispheres. It develops from a very simple group of cells in the embryo and the events that transform the simple structure into the complex human cerebral hemispheres are not well understood. However, when one or many of these events are not taking place, it leads to mild or severe mental retardations. Understanding what these events are and how they shape our brain is therefore very important. This programme of research aims to identify the key events that lead to forebrain formation in vertebrates. It also seeks to discover the particular steps that create the complexity inherent to our mammalian brain. Understanding these steps will show new ways to approach mental retardation and give new tools for stem cell regenerative therapies.

Our lab aims i) to understand the molecular and cellular events that generate forebrain regionalization, ii) to assess their modulation associated to the generation of telencephalic complexity and ii) to identify the mechanisms driving coordination of neuronal differentiation required to develop functional circuits.
The seven hypotheses explored in this programme (listed below) stem from our recent findings concerning cellular behaviour and fate specification inside the neural plate. They aim to understand how signalling centres interact during forebrain regionalisation (Part I) and explore the temporal, cellular and molecular changes that may drive transformation of a zebrafish forebrain neural plate towards a more mammalian one (Part II). It will also assess the coordinating role of the wedge-shaped signalling centre formed across forebrain areas inside the newly formed neural tube (part III). The set of hypotheses are:
Part I:
A. The telencephalon emerges from a BMP-driven repression of an Rx3-controlled eye field identity.
B. Subpallial identity is established by degradation of P-Smad1, via an inhibitory interplay between Fgf and Wnt signalling activities.
C. The anterior diencephalon territory acts as a boundary compartment between ANB and MHB signalling activities.
Part II:
A. The relative extents of telencephalic and diencephalic territories are controlled by temporal, spatial and/or quantitative variation in ANB and MHB induction.
B. The diversity in forebrain complexity may be initiated by size modulation of the forebrain areas during neurulation.
C. The emergence of a cerebral cortex formed by the dorsal telencephalon (pallium) is accomplished by quantitative changes of ANB properties.
Part III: A hard-wired temporal coordination of forebrain neuronal differentiation (formation of a pre-circuit) may be required for the coherent formation of neuronal circuits.
To test these hypotheses, we propose a set of original cellular, molecular and genetic approaches to understand the establishment of forebrain territories in vertebrates. Our ambition is to couple this understanding to the identification of early generators of forebrain complexity. We will use zebrafish and, to a lesser extent, mouse genetics (existing mutants and new mutants produced using in-house zinc finger nuclease targeted mutagenesis), conditional mis-expression (existing CreER and heat inducible transgenic lines), trans-species transplants, high-resolution imaging, and RNA profiling. Forebrain organisation will be analysed using routine markers for neuronal differentiation and axonal connectivity.