Embryonic Neural Progenitor Dynamics in Mouse Models of Down Syndrome

Lay Summary

Building a Better Mouse Model to Study Down’s Syndrome

Researchers aim to use cellular imaging to determine how Down’s syndrome affects stem cells in the developing brain in a new animal model, and then determine how altered stem cell development relates to the behavioral abnormalities that the animals exhibit following birth.

A mouse model referred to as “Ts65Dn” is an exact genetic replica of human Down’s syndrome and exhibits behavioral abnormalities after birth.  These mice are difficult to breed in the laboratory.  With the Down’s syndrome hallmark of three copies of a gene on chromosome 21, and behavioral dysfunctions, the model represents a substantial advantage over the existing “Down’s syndrome-like” mouse model.  The two disadvantages of the existing model are that it is an inexact replica and the immediate death after birth of the laboratory mice precludes any behavioral study.  However, the existing model has provided evidence that stem cells in the brain do not divide normally during embryonic development.  This abnormality delays growth of cells in the brain’s cortex, and compromises neuronal connections between the cortex and the rest of the brain before birth.

With the new Ts65Dn animal model, scientists would be able to confirm these abnormal stem cell findings and their effects on neural connections in an exact genetic animal model replica of the human disease.  They also would be able to correlate the brain abnormalities with behavioral dysfunctions in the animals following birth.

To date, with feasibility funding from Dana, the researchers have been able to make progress in breeding the mice.   Phase II funding of $100,000 will enable the investigators to complete the breeding of enough mice to conduct their imaging and behavioral studies.

If Phase II is successful, researchers will receive Phase III funding of $100,000 to use multi-photon microscopy to determine the effects of aberrant stem cell division on brain cell growth and connectivity, and relate these findings to the animals’ abnormal behaviors.

Significance:  Cellular imaging in this animal genetic replica of human Down’s syndrome could provide vital information on how this devastating developmental disorder occurs in the brain.

Abstract

Embryonic Neural Progenitor Dynamics in Mouse Models of Down Syndrome

Cognitive performance depends, in large part, on proper prenatal development of the cerebral cortex. Specifically, multiple events during embryonic cortical growth, such as neurogenesis, migration, and differentiation, must proceed in a synchronous fashion to enable proper connections between the cortex and other brain structures. The role that early neurogenic events play in overall cortical development will be studied using two animal models of Down syndrome (DS): the trisomy 16 (Ts16) mouse and the Ts65Dn mouse.

The comparison of these two DS models is important since embryonic development has been well described only in Ts16 mice. Our previous studies have shown that neocortical development in Ts16 is profoundly delayed due to abnormalities in stem and progenitor cell division. Moreover, this delay in growth results in reduced innervation of the cortex during the neonatal period. Unfortunately, unlike human DS patients, Ts16 animals do not survive birth and cannot be studied behaviorally. Conversely, Ts65Dn animals do survive birth and live to old age. However, since Ts65Dn animals are costly and difficult to breed, researchers have been unwilling to terminate pregnancies and so most of the work on Ts65Dn has been focused on postnatal development and behavioral analyses. Thus, while both models share genetic and phenotypic similarities to human DS patients, there is currently no model of Down syndrome that has been characterized both prenatally and postnatally.

Here we propose to develop colonies of Ts16 and Ts65Dn mice specifically to compare their embryonic cortical development. Using classical neuroanatomical studies in combination with cutting edge methods for in utero transfection of progenitor cells and time lapse multiphoton imaging, the proposed studies will characterize Ts65Dn embryonic development. This will allow a full embryonic characterization of the changes that result in cognitive dysfunction in these animals later in life. These studies will therefore allow novel future studies correlating abnormal neocortical growth with behavior in a model of DS.