Abstract
The homeobox-encoding gene Prox1 and its Drosophila homologue prospero are key regulators of cell fate-specification. In the developing rodent cortex a sparse population of cells thought to correspond to late-generated cortical pyramidal neuron precursors expresses PROX1. Using a series of transgenic mice that mark cell lineages in the subcortical telencephalon and, more specifically, different populations of cortical interneurons, we demonstrate that neurons expressing PROX1 do not represent pyramidal neurons or their precursors but are instead subsets of cortical interneurons. These correspond to interneurons originating in the lateral/caudal ganglionic eminence (LGE/CGE) and a small number of preoptic area (POA)-derived neurons. Expression within the cortex can be detected from late embryonic stages onwards when cortical interneurons are still migrating. There is persistent expression in postmitotic cells in the mature brain mainly in the outer cortical layers. PROX1+ve interneurons express neurochemical markers such as calretinin, neuropeptide Y, reelin and vasoactive intestinal peptide, all of which are enriched in LGE/CGE- and some POA-derived cells. Unlike in the cortex, in the striatum PROX1 marks nearly all interneurons regardless of their origin. Weak expression of PROX1 can also be detected in oligodendrocyte lineage cells throughout the forebrain. Our data show that PROX1 can be used as a genetic lineage tracer of nearly all LGE/CGE- and subsets POA-derived cortical interneurons at all developmental and postnatal stages in vivo.
Highlights
GABAergic interneurons in rodents originate from subpallial regions in the embryonic telencephalon and migrate widely to populate the neocortex, hippocampus, striatum and amygdala [1,2,3]
At E12.5, E14.5 and E16.5 PROX1 could be detected in the subventricular zone (SVZ) of the medial ganglionic eminence (MGE), the LGE/CGE and the preoptic area (POA) (Fig. 1A–F)
These were few in number and were located mainly within the SVZ and largely absent from the cortical plate (CP) and marginal zone (MZ) (Fig. 1G)
Summary
GABAergic interneurons in rodents originate from subpallial regions in the embryonic telencephalon and migrate widely to populate the neocortex, hippocampus, striatum and amygdala [1,2,3]. Genetic lineage tracing has shown that there are three sources of cortical interneurons in the subpallium: the medial ganglionic eminence (MGE), the lateral/caudal ganglionic eminence (LGE/ CGE) and the preoptic area (POA) [4,5,6,7,8,9,10,11] Each of these regions generates interneurons with distinct physiological, morphological and molecular characteristics, all of which are further sculpted by local connectivity and network recruitment [1]. SOX6 and the recently reported SATB1 transcriptional modulators have been shown to act downstream of LHX6 conferring maturation and network integration of MGE interneuron subtypes [14,15,16,17] These and other markers have shed light on the genetics of cortical interneuron development but have served as invaluable lineage tracers in in vitro stem cell differentiation and in vivo transplantation studies where differentiated cell types need to be identified [18,19,20]
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