TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons

Xavier Caubit (1) , Paolo Gubellini (1) , Joris Andrieux (2) , Pierre L. Roubertoux (3) , Mehdi Metwaly (1) , Bernard Jacq (1) , Ahmed Fatmi (1) , Laurence Had-Aissouni (1) , Kenneth Y. Kwan (4, 5) , Pascal Salin (1) , Michèle Carlier (6) , Agne Liedén (7) , Eva Rudd (7) , Marwan Shinawi (8) , Catherine Vincent-Delorme (9) , Jean-Marie Cuisset (10) , Marie-Pierre Lemaitre (10) , Fatimetou Abderrehamane (2) , Benedicte Duban (11) , Jean-François Lemaître (11) , Adrian S. Woolf (12) , Detlef Bockenhauer (13) , Dany Severac (14) , Emeric Dubois (14) , Ying Zhu (4) , Nenad Sestan (4) , Alistair N. Garratt (15) , Lydia Kerkerian-Le Goff (1) , Laurent Fasano (1)

1 IBDM - Institut de Biologie du Développement de Marseille
2 Institut de Génétique Médicale [CHRU Lille]
3 GMGF - Génétique Médicale et Génomique Fonctionnelle
4 YSM - Yale School of Medicine [New Haven, Connecticut]
5 MBNI - Molecular and Behavioral Neuroscience Institute
6 LPC - Laboratoire de psychologie cognitive
7 Karolinska University Hospital [Stockholm]
8 Washington University School of Medicine in St. Louis
9 Hôpital Jeanne de Flandres
10 Hôpital Roger Salengro [Lille]
11 Hôpital Saint Vincent de Paul de Lille
12 University of Manchester [Manchester]
13 UCL - University College of London [London]
14 IGF MGX - Institut de Génomique Fonctionnelle - Montpellier GenomiX
15 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]

TSHZ3, which encodes a zinc-finger transcription factor, was recently positioned as a hub gene in a module of the genes with the highest expression in the developing human neocortex, but its functions remained unknown. Here we identify TSHZ3 as the critical region for a syndrome associated with heterozygous deletions at 19q12-q13.11, which includes autism spectrum disorder (ASD). In Tshz3-null mice, differentially expressed genes include layer-specific markers of cerebral cortical projection neurons (CPNs), and the human orthologs of these genes are strongly associated with ASD. Furthermore, mice heterozygous for Tshz3 show functional changes at synapses established by CPNs and exhibit core ASD-like behavioral abnormalities. These findings highlight essential roles for Tshz3 in CPN development and function, whose alterations can account for ASD in the newly defined TSHZ3 deletion syndrome.

Mots clés: Neurodevelopmental disorders; Gene regulation; Neuroscience; Neurogenesis

Domaines: Psychologie; Biologie cellulaire; Biologie du développement; Neurosciences [q-bio.NC]

Xavier Caubit, Paolo Gubellini, Joris Andrieux, Pierre L. Roubertoux, Mehdi Metwaly, et al.. TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons. Nature Genetics, 2016, 48 (11), pp.1359-1369. ⟨10.1038/ng.3681⟩. ⟨hal-01432295⟩