UniTs-Neurobiology Degree Neuroembryology II course, AY 2014-2015 A.Mallamaci, SISSA

lesson 6: (1) origin and migration of layer I neurons (2) origin and migration of cortical interneurons

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origin and migration of layer I neurons

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(1) Bayer & Altmann (1991) classically assume that common precursors located in the dorsal telencephalic wall give rise to the entire neocortical neuronal complement.

(2) more recently, it has been demonstrated that more and more laminar neuronal sub-populations derive from dedicated ancestors located outside the dorsal telencephalon. In rodents, these subpopulations are: - Interneurons (located throughout the cortex, generated by MGE and CGE) - Cajal-Retzius cells (located in layer I, generated by CH, VP and septum) [further subpopulations originating outside the pallium have been also described in rodents and humans]

(3) conversely, genetic labelling of glutamatergic neurons via an Emx1-driven cre transgene (Rubenstein, 2004) firmly proved that the almost totality of cortical glutamatergic neurons are generated by precursors expressing Emx1, so located within the dorsal telencephalic wall.

are cortical neurons all generated by precursors located within the dorsal telencephalic wall?

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neurons form exogenous sources: mouse layer I Cajal-Retzius cells generation of Cajal-Retzius by specialized regions of the telencephalon was originally proposed by G. Mayer on the basis of the accurate time course analysis of murine and human embryonic samples (1999, 2002, 2004).

occurrence of these phenomena in the mouse was formally proven by the groups of Y.Tanabe (2004) and A.Pierani (2005).

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Cajal-Retzius cells from the cortical hem

Tanabe and collaborators co-electroporated a tracer lacZ-expressor plasmid and a CR-marker plasmid (expressing EGFP under the control of a promoter which specifically fires in CR-cells) into the E11.5 telencephalon, at different locations.

After a few days, they studied the resulting distribution of the two markers and could prove that: (1) CR-cells are specifically generated by the cortical hem as well as - to a minor extent - by the antero-medial telencephalic pole; (2) therefrom, they tangentially diffuse to far locations.

Accurate time course analysis of the system suggested that hem-generated CR-cells spread all over the telencephalon, playing a major role in the coverage of dorsal, caudal-medial regions of it. 5

Cajal-Retzius cells from ventral pallium and septum

A.Pierani and collaborators found that the homeogene Dbx1 is specifically expressed by ventral pallium and septum

in order to follow the fate of the descendants of these Dbx1-expressing cells, they alternatively knocked into the Dbx1 locus two different cds: (1) nsl-lacZ, whose protein product, more stable than Dbx1, allows mid-term chasing of these progenies (2) cre, whose protein product may allow irreversible functional activation of an nls-lacZ cds born by another transgene, constitutively transcribed but basally silent as preceded by a floxed STOP cassette

extensive co-localisation of beta-gal and Reln occurring in telencephala of the resulting mice mutants allowed to prove that CR-cells covering paleocortex and lateral neocortex derive to large extent from the two Dbx1-expressing districts described above. 6

apparent functional redundance of the different sources of CR-cells_I

the group of A. Pierani (2005) genetically ablated ventral pallium and septum, by intersectional DT-A mutagenesis, but could not get a reeler phenotype.

this was reasonably due to partial working of the ablation system as well as to the replace-ment of non-hem derived CR-cells by hem-derived ones, massively occurring by E14.5

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NB. Dbx1 promoter restricts the manipulation to ventral pallium-derivatives; Nes promoter restricts cre expression to apical precursors

apparent functional redundance of the different sources of CR-cells_II

the group of E.Grove (2005) genetically ablated the cortical hem, again by intersectional DT-A mutagenesis, but was not able to get a reeler phenotype.

in this case, non-hem derived CR-cells hardly replaced hem-derived ones, because of their modest spreading to dorso-medial territories occurring in Wnt3axneoxdta/+Emx1IREScre/+ mutants.

moreover, the secondary source of Reln which appears in presumptive layers V-IV starting from E14.5-E15.5, was not impaired in these mutants.

as a consequence of that, no reeler phenotype was observed 8

neurons form exogenous sources: human layer I neurons

Bystron et al (2006) re-analyzed the genesis of layer I in the human cortex and found a scenario considerably much more complex than in rodents. She described four neuronal subtypes, two generated by local precursors (“locally generated” and Cajal-Retzius, ???), two generated elsewhere (predecessor and olfactory epithelium derivatives). The biological meaning of all that is obscure.

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