Lmx1a regulates fates and location of cells originating from the cerebellar rhombic lip and telencephalic cortical hem

Abstract

The cerebellar rhombic lip and telencephalic cortical hem are dorsally located germinal zones which contribute substantially to neuronal diversity in the CNS, but the mechanisms that drive neurogenesis within these zones are ill defined. Using genetic fate mapping in wild-type and Lmx1a −/− mice, we demonstrate that Lmx1a is a critical regulator of cell-fate decisions within both these germinal zones. In the developing cerebellum, Lmx1a is expressed in the roof plate, where it is required to segregate the roof plate lineage from neuronal rhombic lip derivatives. In addition, Lmx1a is expressed in a subset of rhombic lip progenitors which produce granule cells that are predominantly restricted to the cerebellar posterior vermis. In the absence of Lmx1a , these cells precociously exit the rhombic lip and overmigrate into the anterior vermis. This overmigration is associated with premature regression of the rhombic lip and posterior vermis hypoplasia in Lmx1a −/− mice. These data reveal molecular organization of the cerebellar rhombic lip and introduce Lmx1a as an important regulator of rhombic lip cell-fate decisions, which are critical for maintenance of the entire rhombic lip and normal cerebellar morphogenesis. In the developing telencephalon Lmx1a is expressed in the cortical hem, and in its absence cortical hem progenitors contribute excessively to the adjacent hippocampus instead of producing Cajal-Retzius neurons. Thus, Lmx1a activity is critical for proper production of cells originating from both the cerebellar rhombic lip and the telencephalic cortical hem.

The cortical hem regulates the size and patterning of neocortex

“…First, the cortical hem regulates broad patterning of the cerebral cortex along the D/V axis, promoting dorsal cortical identity and suppressing ventral identity, reminiscent of the actions of the roofplate in the caudal neural tube. Similar to signals from the roofplate, hem signals direct both cell proliferation and the adoption of specific regional identities (Chizhikov et al, 2010;Galceran et al, 2000;Lee et al, 2000b;Liem et al, 1997;Mangale et al, 2008;Megason and McMahon, 2002). Dorsomedial neocortex is reduced in the hem-ablated mouse, because of transiently decreased cell proliferation probably caused by loss of WNT signaling from the hem.…”

Development of the cerebellum: simple steps to make a ‘little brain’

“…Atoh1-positive cells at the interface between these two zones are largely glutamatergic (Machold and Fishell, 2005;Wang et al, 2005;Rose et al, 2009). However, blurring is seen when genetic labelling with Lmx1a-and Gdf7-driven Cre lines, which might be expected to be confined to the roof plate and its choroid plexus derivative, is also found unexpectedly in both glutamatergic and GABAergic descendants (Chizhikov et al, 2010;Cheng et al, 2012). This is significant in that it could suggest that lineages are not restricted.…”

“…This is significant in that it could suggest that lineages are not restricted. Furthermore, this blurring is increased on deletion of Lmx1a (Chizhikov et al, 2010), whereas genetic deletion of either Ptf1a or Atoh1 leads to increased mixing of lineages ( Fig. 5C-E) (Wang et al, 2005;Pascual et al, 2007;Millen et al, 2014) due to the mutually repressive functions of these genes (Yamada et al, 2014).…”

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…Downstream BMP signaling through Lmx1a plays a unique role in segregating roof plate epithelium lineage from adjacent cerebellar rhombic lip cell lineage. Lmx1a 2/2 mouse embryos induce the roof plate normally; however, cells that belong to the roof plate epithelium lineage migrate and adopt fates of neuronal rhombic lip derivatives (Chizhikov et al 2010). Msx1 signals downstream of BMP in the more rostral roof plate, and targeted inactivation of Msx1 causes a specific loss of the diencephalic roof plate and compromises the dorsal subcommissural organ (Bach et al 2003).…”