Overexpression of MATH1 disrupts the coordination of neural differentiation in cerebellum development

An essential role for the bHLH transcription factor MATH1 in the formation of cerebellar granule cells was previously demonstrated in a Math1 null mou se. The function of regulated levels of MATH1 in granule cell development i s investigated here using a gain-of-function paradigm. Overexpression of Ma th1 in its normal domain in transgenic mice leads to early postnatal lethal ity and perturbs cerebellar development. The cerebellum of the (B)MATH1 tra nsgenic neonate is smaller with less foliation, particularly in the central vermal regions, when compared to wild-type cerebella. A detailed analysis of multiple molecular markers in brains overexpressing Math1 has revealed d efects in the differentiation of cerebellar granule cells. NeuroD and doubl ecortin, markers normally distinguishing the discrete layered organization of granule cell maturation in the inner EGL, are aberrantly expressed in th e outer EGL where MATH1-positive, proliferating cells reside. In contrast, TAG-1, a later marker of developing granule cells that labels parallel fibe rs, is severely diminished. The elevated MATH1 levels appear to drive expre ssion of a subset of early differentiation markers but are insufficient for development of a mature TAG-1-expressing granule cell. Thus, balanced leve ls of MATH1 are essential for the correct coordination of differentiation e vents in granule cell development.