The engrailed homeobox genes are required in multiple cell lineages to coordinate sequential formation of fissures and growth of the cerebellum

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Abstract

The layered cortex of the cerebellum is folded along the anterior-posterior axis into lobules separated by fissures, allowing the large number of cells needed for advanced cerebellar functions to be packed into a small volume. During development, the cerebellum begins as a smooth ovoid structure with two progenitor zones, the ventricular zone and upper rhombic lip, which give rise to distinct cell types in the mature cerebellum. Initially, the cerebellar primordium is divided into five cardinal lobes, which are subsequently further subdivided by fissures. The cellular processes and genes that regulate the formation of a normal pattern of fissures are poorly understood. The engrailed genes (En1 and En2) are expressed in all cerebellar cell types and are critical for regulating formation of specific fissures. However, the cerebellar cell types that En1 and En2 act in to control growth and/or patterning of fissures has not been determined. We conditionally eliminated En2 or En1 and En2 either in both progenitor zones and their descendents or in the two complementary sets of cells derived from each progenitor zone. En2 was found to be required only transiently in the progenitor zones and their immediate descendents to regulate formation of three fissures and for general growth of the cerebellum. In contrast, En1 and En2 have overlapping functions in the cells derived from each progenitor zone in regulating formation of additional fissures and for extensive cerebellar growth. Furthermore, En1/2 function in ventricular zone-derived cells plays a more significant role in determining the timing of initiation and positioning of fissures, whereas in upper rhombic lip-derived cells the genes are more important in regulating cerebellar growth. Our studies reveal the complex manner in which the En genes control cerebellar growth and foliation in distinct cell types.

Highlights

► Requirement for En1 and En2 in the cerebellum progenitor zone lineages was studied. ► En1/2 are required in ventricular zone-derived cells primarily for foliation. ► En1/2 are required in upper rhombic lip-derived cells primarily for growth. ► En2 alone is required mainly in progenitor cells for cerebellum growth and foliation. ► En1/2 together have multiples functions in growth and formation of fissures.

Abbreviations

VZ
ventricular zone
RL
rhombic lip
DCN
deep cerebellar nuclei
gcs
granule cells
gcps
granule cell precursors
IGL
internal granule cell layer
EGL
external granule cell layer
pc
preculminate
ppy
prepyramidal
pr
primary
prc
precentral
sec
secondary
po
posterolateral
μm
micrometer

Keywords

En1 and En2
Brain development
Foliation
Transcription factors
Patterning
Conditional knockouts
CRE

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