Cerebellar GABAergic progenitors adopt an external granule cell-like phenotype in the absence of Ptf1a transcription factor expression

Abstract

We report in this study that, in the cerebellum, the pancreatic transcription factor Ptf1a is required for the specific generation of Purkinje cells (PCs) and interneurons. Moreover, granule cell progenitors in the external GCL (EGL) appear to be unaffected by deletion of Ptf1a. Cell lineage analysis in Ptf1a Cre/Cre mice was used to establish that, in the absence of Ptf1a expression, ventricular zone progenitors, normally fated to produce PCs and interneurons, aberrantly migrate to the EGL and express typical markers of these cells, such as Math1, Reelin, and Zic1/2. Furthermore, these cells have a fine structure typical of EGL progenitors, indicating that they adopt an EGL-like cell phenotype. These findings indicate that Ptf1a is necessary for the specification and normal production of PCs and cerebellar interneurons. Moreover, our results suggest that Ptf1a is also required for the suppression of the granule cell specification program in cerebellar ventricular zone precursors.cerebellum ͉ GABAergic cells ͉ neural specification

LIM-homeodomain proteins Lhx1 and Lhx5, and their cofactor Ldb1, control Purkinje cell differentiation in the developing cerebellum

“…Survival of Purkinje cells is mediated by genes encoding nuclear factors Ror-␣ (42, 43) and Nna1 (44), and by neurotrophic factors such as the nerve growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor, neurotrophin-4/5, and acetylcholine (45,46). Most recently, the transcription factor Ptf1a has been shown to be required for the specification of progenitors of all GABAergic neurons, including Purkinje cells in the ventricular zone of the developing cerebellum (18,19). Our studies went beyond these analyses in defining factors such as Lhx1 and Lhx5 that were directly involved in Purkinje cell differentiation.…”

“…10F). In contrast to calbindin, Pax2, a marker for cerebellar GABAergic interneurons such as the basket and stellate cells (19,37), was detected in many cells of the Lhx1/Lhx5 double mutants as well as in the controls at E14.5 ( Fig. 2 I and J) and E18.5 ( Fig.…”

“…[14][15][16][17]. Recent studies have revealed that Ptf1a, a basic helix-loop-helix transcription factor, is required for the specification of progenitors of all cerebellar GABAergic neurons, including Purkinje cells, in the ventricular zone of the cerebellum (18,19). However, the factors that regulate further differentiation of Purkinje cells after they become postmitotic and migrate out of the ventricular zone have remained unclear.…”

Besides Purkinje cells and granule neurons: an appraisal of the cell biology of the interneurons of the cerebellar cortex

“…In contrast, initial formation of granule cell precursors in the nascent external granule cell layer is not aVected by mutating this gene actually, as elegantly shown by Pascual et al (2007) lack of Ptf1a does not result in a failure of GABAergic precursors to form, or to their demise, but redirects these cells to acquire an excitatory, external granule cell layer fate. The fate and development of (purely) glycinergic cerebellar neurons (i.e., type 5 Golgi cells according to Simat et al (2007) has not been analyzed in Ptf1a-null mice.…”

Cerebellar development and disease

“…In the absence of Ptf1a, cerebellar VZ fails to generate all of the known GABAergic cerebellar neuronal subtypes including Purkinje cells (PCs), stellate and basket cells and a subset of deep cerebellar neurons, which constitute the main outflow tract of the cerebellum [7,8]. Fate mapping of Ptf1a+ cells in wild-type mice demonstrates that Ptf1a+ VZ cells are normally fated to produce all of these GABAergic cerebellar cell types and thus, their loss is caused by a primary failure of the VZ to produce appropriate neurons in the absence of Ptf1a.…”