Impact of Dlx2 and Isl1 overexpression on neuroblasts generated in a mouse toxic model of Huntington's disease

Huntington’s disease is a neurodegenerative inherited disorder caused by a genetic mutation in the huntingtin gene leading to aberrant expansion of the trinucleotide CAG repeat at the N-terminal of the protein. The mutation leads to neuronal loss, primarily the medium spiny neurons (MSNs) of the striatum; and progressively spreads to cortical neurons as the disease advances, resulting in impaired movement control, behavioral changes, and cognitive decline. While there has been progress in understanding the neuropathological mechanisms underlying the disease, the inability to counteract neuronal degeneration remains a challenge to be addressed to improve the life of patients. Quinolinic acid (QA) injection into the striatum of animal experimental models induces a massive loss of MSNs via receptor-mediated excitotoxicity making its application suitable to recapitulate the neurodegenerative phenotype. Previous work has demonstrated that after QA lesion striatal astrocytes undergo neurogenic activation generating a large pool of neurons through the production of transient amplifying progenitors. However, newly formed neuroblasts are not committed to a MSN identity and have a transient lifespan rendering them unsuitable for sustained repair through the reconstruction of damaged circuits. To overcome this limitation, we aimed to instruct lesion-induced neuronal progenitors and their progeny to acquire an MSN phenotype by in vivo overexpression of DLX2 and ISL1 TFs that during development promote a GABAergic phenotype and the acquisition of a D1 MSN subtype, respectively. Immunohistochemistry analyses revealed that the tested cocktail of transcription factors did not properly induce reprogrammed cells to express MSN markers. However, we found a modest impact of DLX2 overexpression on the morphology of the transduced neurons. Albeit the combination of DLX2 and ISL1 is not sufficient to induce a fully mature striatal phenotype, DLX2 might have a role in accelerating cell maturation of the newly formed neuroblasts. Further combinations of transcription factors important for striatal commitment and cell survival may enhance the acquisition of more complex morphology and mature marker expression.