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 mouse. The function of regulated levels of MATH1 in granule cell development is investigated here using a gain-of-function paradigm. Overexpression of Math1 in its normal domain in transgenic mice leads to early postnatal lethality and perturbs cerebellar development. The cerebellum of the (B)MATH1 transgenic 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 defects in the differentiation of cerebellar granule cells. NeuroD and doublecortin, markers normally distinguishing the discrete layered organization of granule cell maturation in the inner EGL, are aberrantly expressed in the outer EGL where MATH1-positive, proliferating cells reside. In contrast, TAG-1, a later marker of developing granule cells that labels parallel fibers, is severely diminished. The elevated MATH1 levels appear to drive expression of a subset of early differentiation markers but are insufficient for development of a mature TAG-1-expressing granule cell. Thus, balanced levels of MATH1 are essential for the correct coordination of differentiation events in granule cell development.
Helms
A W
AW
Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Gowan
K
K
Abney
A
A
Savage
T
T
Johnson
J E
JE
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D015816:Cell Adhesion Molecules, Neuronal; D002454:Cell Differentiation / Q000502:physiology; D002531:Cerebellum / Q000002:abnormalities* / Q000166:cytology*; D058969:Contactin 2; D000089622:Doublecortin Domain Proteins; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D005804:Genes, Lethal; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics; D009474:Neurons / Q000737:chemistry / Q000166:cytology*; D009479:Neuropeptides / Q000032:analysis / Q000235:genetics; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics*
D051792:Basic Helix-Loop-Helix Proteins; D015816:Cell Adhesion Molecules, Neuronal; D058969:Contactin 2; D000089622:Doublecortin Domain Proteins; D008562:Membrane Glycoproteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D014157:Transcription Factors; C500943:Atoh1 protein, mouse; C548675:Cntn2 protein, mouse; C093564:Neurogenic differentiation factor 1