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Dmrt5 is controlled by negative autoregulation and has autonomous effects on hippocampus development and neocortex arealization

par De Clercq, Sarah ;Keruzore, Marc ;Pollart, Charlotte ;Assimacopoulos, Stavroula;Preillon, Julie ;Ascenzo, Sabrina ;Matson, Clinton K;Hochepied, Tino;Zarkower, David;Grove, Elizabeth
Référence ISDN meeting "From stem cells to behaviour in the normal and diseased nervous(21th: 11-14 May: Antibe), Dmrt5 is controlled by negative autoregulation and has autonomous effects on hippocampus development and neocortex arealization
Publication A Paraître, 2016

Abstract de conférence

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Résumé :

Patterning of the cerebral hemispheres and arealization of the neocortex depends initially on interplay between morphogens secreted by organizing centers and transcription factors expressed in gradients across the cortical primordium. One of these, Dmrt5/Dmrta2, a zinc finger doublesex and mab-3 related (Dmrt) gene, is expressed in mouse cortical progenitors in a high caudomedial to low rostrolateral gradient. Dmrt5 is required for the development of the caudomedial part of the cerebral cortex but its mode of action remains unclear. In Dmrt5 null mice, the caudomedial cortical organizing center, the Wnt-and Bmp rich cortical hem, is greatly reduced, implying that hem formation relies on DMRT5 activity, and that loss of Dmrt5 affects caudomedial cortex via decreased hem signalling. In a positive feedback loop however, WNT signalling upregulates Dmrt5 expression, suggesting a downstream patterning role for DMRT5. Here we investigated the latter role by inactivating Dmrt5 conditionally in dorsal telencephalon progenitors, and by generating conditional Dmrt5 gain-of-function transgenic mice. In each mouse line, WNT and BMP signaling at the hem appeared largely unaffected. In these conditional mutants, the hemispheres were however smaller than in controls, and the hippocampus and primary visual area (V1) of the neocortex were sharply reduced. No such defects were observed in Dmrt5 hem specific ablated mice. While heterozygous Dmrt5 null mice show a similar reduction of V1 area, opposite changes are observed when Dmrt5 was overexpressed from midgestation onwards. In each mouse line, expression levels of the cortical patterning genes Emx2, Lhx2, and Pax6 were altered. Dmrt5 expression itself was perturbed revealing that it is controlled by negative feedback autoregulation. Together, our findings reveal that DMRT5 levels are tightly controlled and have autonomous effects on hippocampal development and neocortical arealization.