Role of the transcription factor Isl1 in forebrain dopaminergic neuron identity

CAMARANO AC; RUBINSTEIN M; DE SOUZA FS

Chascomus

Taller; V Taller de Biología Celular y de Desarrollo; 2022

Dopaminergic (DA) neurones of the ventral midbrain have been extensively characterised, but the populations of forebrain neurones that also produce this neurotransmitter have received far less attention. These forebrain DA neurones are distributed along the ventral telencephalon, specially in the preoptic area, as well as in the alar and basal hypothalamus up to the limit between the peduncular hypothalamus and the prethalamus. Their functions include the control of the reproductive axis, lactation and energy expenditure, but little is currently known about the genetic factors influencing the development of these neurones. Here, we have identified the LIM-homeodomain Islet1 (Isl1) transcription factor as an early marker for forebrain DA neurones in the mouse. Expression of Isl1 is observed in all populations of tyrosine hydroxylase (TH)-expressing neurons starting at E10.5, and this coexpression persists during development. In adult mice, Isl1 and TH do not colocalise to the same extent except in the A13 population, located in the hypothalamus-prethalamus border, where over 80% of DA neurons also express Isl1. Experiments with genetically-modified mice carrying a floxed Isl1-allele and an tamoxifen-inducible Cre recombinase transgene indicate that Isl1 is necessary for the expression of TH in the early forebrain but not in the midbrain, where Isl1 is not expressed. Interestingly, preliminary experiments where floxed Isl1 alleles are eliminated using a TH-Cre transgene suggest that the loss of Isl1 at later stages does not affect TH expression. This indicates that the requirement for Isl1 in DA neuronal identity changes over time, being crucial only during the early development of these neurones.