Our study shows that bRG cells occur in the SVZ of marmoset, a near-lissencephalic primate, at much greater relative abundance than in the SVZ of mouse (Shitamukai et al. 2011
; Wang et al. 2011
), a lissencephalic rodent, and at similar relative abundance as in the SVZ of human (Fietz et al. 2010
; Hansen et al. 2010
), a gyrencephalic primate, and ferret (Fietz et al. 2010
; Reillo et al. 2011
), a gyrencephalic nonprimate. Previously, the possibility has been discussed that the occurrence of bRG cells in the SVZ at high relative abundance may be an underlying cause of gyrencephaly (Fietz et al. 2010
; Reillo et al. 2011
; Fietz and Huttner 2011
). In this regard, the present data leave us with 2 principal lines of interpretation. First, an abundance of bRG cells may not be linked to the appearance of gyrencephaly. Second, an abundance of bRG cells may be related to the appearance of gyrencephaly, but this relationship is more complex than previously assumed. Specifically, our findings are consistent with the concept that an abundance of bRG cells may be necessary, but is not sufficient, for gyrencephaly, as will be discussed below.
It has been known that the occurrence of bRG cells at high relative abundance does not correlate with the extent of gyrencephaly and of neocortical expansion in general. Thus, bRG cells occur at similar relative abundance in the embryonic ferret and human SVZ (≈50% in either species) (Fietz et al. 2010
; Hansen et al. 2010
; Reillo et al. 2011
), yet the extent of gyrencephaly in these 2 mammals is vastly different. It follows that other parameters, such as the number of cell cycles that each bRG cell undergoes and/or the population size and cell cycle number of progenitor cells downstream of bRG cells (Hansen et al. 2010
), critically determine the extent of gyrencephaly and of neocortical expansion.
Nonetheless, our study offers a possible explanation to reconcile the near-lissencephalic shape of the marmoset neocortex with the occurrence of bRG cells in the SVZ at similar abundance as in the gyrencephalic ferret and human neocortex. Specifically, the marmoset neocortex may be secondarily lissencephalic, perhaps reflecting the marmoset's relatively small body size. In other words, the marmoset may have evolved from a gyrencephalic ancestor by phyletic dwarfing (Ford 1980
) and, due to the reduction in body size, may have been able to retain the same cortical surface-to-body volume ratio as its ancestor by developing a lissencephalic neocortex. Indeed, our analysis of the relationship between various anthropoid species with regard to their GI suggests that a common ancestor of these species would have exhibited a medium-level gyrencephalic neocortex, with some anthropoid species including marmoset subsequently becoming less gyrencephalic and others including human becoming more gyrencephalic (). Thus, while the marmoset's lissencephaly has been viewed as a primitive trait (Stellar 1960
), our evolutionary model suggests that it may well be a derived trait. As a corollary of our concept, an abundance of bRG cells may well be characteristic of primates and other gyrencephalic species if one assumes that this abundance in the near-lissencephalic marmoset neocortex is counteracted by changes in other progenitor cell parameters.
Candidates for such parameters include the population size of neurogenic progenitor cells and the number of neurogenic divisions that each of these progenitor cells undergoes. In this context, we found that the proportion of cycling cells that were in M-phase was lower in embryonic marmoset than developing ferret neocortex. On the assumption that M-phase comprises a similar proportion of the cell cycle in marmoset and ferret neocortical progenitor cells, these data raise the possibility that the cell cycle of marmoset neocortical progenitor cells may be longer than that of ferret. Given that alterations in cell cycle length have been implicated in cortical development and expansion (Götz and Huttner 2005
; Dehay and Kennedy 2007
), it will be important to directly determine the cell cycle length of marmoset neocortical progenitors and compare it with other, lissencephalic and gyrencephalic, primate and nonprimate species.
Another candidate parameter contributing to lissencephaly versus gyrencephaly may be the time course of the change in the relative proportion of SVZ progenitor cells to VZ progenitor cells during neocortical development. Analyzing previous (Fietz et al. 2010
) and present data, we noticed that the preponderance of the SVZ over the VZ in terms of radial thickness follows a different time course in embryonic marmoset compared with embryonic human or ferret ().
Figure 7. Radial thickness ratio of SVZ/VZ during embryonic development of human, ferret, and marmoset neocortex. Radial thickness of the VZ and SVZ was measured using the images shown in Figure 1d–k (human, A) and Figure 1n–s (ferret, B) of Fietz (more ...)
At E92, and even more so at E95 and E100, the cytoarchitecture of the marmoset SVZ, as apparent from DAPI and Tuj1 stainings, allowed us to distinguish between an ISVZ and an OSVZ. Yet, the relative abundance of bRG cells, as apparent from basal process–bearing/Sox2-positive/Tbr2-negative mitoses, was essentially the same for ISVZ and OSVZ. This not only underscores that referring to these progenitor cells as bRG cells rather than OSVZ progenitors or outer RG appears to be appropriate. It also reveals that cytoarchitecture does not necessarily allow one to make reliable predictions as to the abundance of a given progenitor type.
On a more general note, our study constitutes an effort to trace the origins of gross morphological features of the brain to fundamental cellular properties. Our results are consistent with the notion that gyrencephaly may be an evolutionarily labile trait, reflecting, perhaps, the relative ease with which neural progenitor cell parameters can be modified. This notion would be in line with the view that evolution often is a process of “tinkering” with available modules rather than inventing de novo (Jacob 1977
). Given that transgenic techniques for the common marmoset have recently been developed (Sasaki et al. 2009
), the significance of bRG cells for the development of the marmoset neocortex can be addressed by genetic manipulation in the future.