Influence of the Embryonic Preplate on the Organization of the Cerebral Cortex: A Targeted Ablation Model

Abstract

Transgenic mice were generated to permit the targeted ablation of cortical preplate cells at the time they are born. In these mice, the 1.3 kb golli promoter of the myelin basic protein gene was used to drive the herpes simplex virus thymidine kinase (TK) transgene in cortical preplate cells. Heterozygous transgenic pairs were bred, and pregnant dams were treated with ganciclovir at embryonic days 11-12 to ablate preplate cells at the time the preplate was forming. This paradigm exposed control (TK-) and experimental (TK+) littermates to exactly the same conditions. Embryological ablation of preplate cells led to an early disruption of the radial glial framework and subplate structure in the developing cortex and dramatically altered the cellular lamination and connectivity of the cortical plate. The disturbed radial glial network contributed to an impaired radial migration of neurons into the cortical plate from the ventricular zone. The cortical plate became dyslaminated, and there was a substantial reduction in short- and long-range cortical projections within the cortex and to subcortical regions. Cell death within the cortical plate and the proliferative zones was substantially increased in the ablated animals. After birth, a cortical lesion developed, which became exacerbated with the secondary onset of hydrocephaly in the second postnatal week. The results underscore the critical importance of the preplate in cortex formation, mediated through its guidance of the formation of radial glial scaffolding, subsequent neuronal migration into the incipient cortical plate, and the final arrangement of its vertical organization and cellular connectivity.

High Levels of Cre Expression in Neuronal Progenitors Cause Defects in Brain Development Leading to Microencephaly and Hydrocephaly

“…Interestingly, all of the features described in these models as well as in other animal models of impaired neurogenesis, such as specific ablation of radial glia (Xie et al, 2002) or loss-of-function of genes involved in neuronal migration or adhesion (Ramanathan et al, 1996;Fransen et al, 1998;Bearer, 2001;Assadi et al, 2003;Sakata-Haga et al, 2004), were recapitulated at different levels in our homozygous NLSCre Bal1 mice or in the heterozygous Cre-ER T2 models. This suggests that impairment of nestin-positive cell populations either by specific genes removal or through Cremediated toxicity may lead to similar defects.…”

“…4 A, B). This suggested that the ensuing development of hydrocephalus could be secondary to a reduction in the number of progenitors reaching the cortical plate (Xie et al, 2002;Assadi et al, 2003).…”

Neuronal Birthdate-Specific Gene Transfer with Adenoviral Vectors

“…8). A recent study using a transgenic mouse that expresses the HSVtk gene specifically on C-R cells and subplate neurons also indicated that the ablation of C-R cells and subplate neurons causes a reduction in brain size and abnormal laminar formation (Xie et al, 2002). Accordingly, the abnormal phenotype of the manipulated brain appears to be caused by the ablation of the subset of C-R cells and subplate neurons.…”

Recovery of Myelin after Induction of Oligodendrocyte Cell Death in Postnatal Brain

“…The expression of an inducible toxicity gene, thymidine kinase of the herpes simplex virus-1 (HSV1-TK), has been successfully used to target a wide number of cells in vivo and in vitro (Caruso and Klatzmann, 1992;Wallace et al, 1994;Bush et al, 1998;Xie et al, 2002;Fillat et al, 2003). Indeed, the thymidine kinase (TK) system is based on the capacity of the HSV1-TK to phosphorylate certain nucleoside analogs such as ganciclovir (GCV) (Heyman et al, 1989;Salomon et al, 1994;Delaney et al, 1996).…”