Stem cells with delayed neurogenesis and the evolution of callosal interhemispheric connections in the mammalian brain

Understanding development and evolution of the neocortex has important implications. Differential timing of developmental events sculpts the brains of different species into distinct organs. The latest investigations on the development of the dorsal forebrain in chick and mouse embryos showed a major difference between vertebrate brains. A delay in the neurogenic properties of a subset of progenitors is specific to mammals and could be responsible for the evolutionary origin of the corpus callosum.

HFSP Long-Term Fellow Fernando García-Moreno and Program Grant holder Zoltán Molnár
authored on Mon, 31 August 2015

HFSP fellow Fernando García-Moreno and Research Grant alumnus Zoltán Molnár have published a paper in PNAS showing an interesting divergence of the embryonic development of the forebrain of vertebrate species. During the embryonic generation of the mammalian neocortex, the stem/progenitor cells generate several types of neurons progressively. It has been widely believed that most cortical progenitors contribute to most layers in a stereotyped sequence.  However, García-Moreno and Molnár showed a new type of progenitor cell in the mouse brain that did not generate the expected neuronal lineage. They discovered that these progenitors can be selectively labelled by means of a specific promoter sequence (Emx2) and demonstrated that these cells showed delayed neurogenesis (Figure 1 upper panels). These progenitors only became neurogenic after several days, when they give rise to a restricted lineage comprising neurons for the upper layer of the cortex and glial cells only. An unspecific general promoter sequence labelled progenitors that started neurogenesis immediately after labelling and contributed to all layers.  When the authors investigated the neuronal lineage of the homologous stem cells in chick embryos they found no evidence of any similar neurogenic delay (Figure 1 lower panels). Consequently, these chick forebrain stem/progenitor cells did not restrict their neuronal lineage in chick embryo and behaved in the same way as all other progenitors of the dorsal forebrain.

Figure 1: Mammalian but not avian forebrain stem/progenitor cells labelled through Emx2 promoter sequence show delayed neurogenesis.
Top row - examples of the distribution of the cortical neurons in mouse E14, 2 days after electroporation with general and Emx2 promoter construct at E12.
Bottom row - chick cases at E6, 2 days after electroporation at E4.
Left column – labelled with EGFP, early progenitors of the forebrain generated neurons that migrated to the postmitotic areas (CP: cortical plate; MZ: mantle zone).
Right – also labelled with EGFP, early progenitors selected by their expression of Emx2 did not generate neurons in mouse (observe the absence of green cells in CP) but were neurogenic in chick (green cells were present in MZ).





These new data suggest that the early embryonic mammalian neocortex hosts several types of progenitor cells that generate a different lineage. But also, it carries important evolutionary implications. The mammalian delayed progenitors give rise to the callosal neurons that connect the two cortical hemispheres (Figure 2).

Figure 2: The lineage derived from early delayed progenitors (green cells on the left) generate projections travelling in the white matter to form the corpus callosum (right).

The corpus callosum was undoubtedly a major evolutionary advantage by providing interhemispheric cooperation and specialisation and it is only present in mammalian brains. Since chicks lack both the corpus callosum and the delayed neurogenesis of forebrain progenitors, García Moreno and Molnár propose that these two events might be intimately associated and drove mammalian brain evolution (Figure 3). Therefore the discovery of these progenitors with neurogenic delay represent an important step in our understanding of both mammalian neocortical development and evolution.

Figure 3: Schematic summary of the differences found in the development of the dorsal forebrain in mouse and chick. In mouse cortex there are progenitors that contribute to all layers and an early delayed progenitor subtype that mostly contributes to upper layers.  In chick there is no such distinction between the differentially labelled progenitors.


Subset of early radial glial progenitors that contribute to the development of callosal neurons is absent from avian brain. García-Moreno and Molnár Z.  (2015). PNAS August 25, 2015.doi: 10.1073/pnas.1506377112.

Link to article

Pubmed link