CDB Seminar - Dr Eduardo Leyva-Díaz, Instituto de Neurociencias, CSIC-UMH

Please join us for a CDB Seminar by Dr Eduardo Leyva-Díaz, Instituto de Neurociencias, CSIC-UMH.

‘Programming and reprogramming the nervous system via CUT homeobox genes’

Thursday, 13th March 2025, 1:00pm-2:00pm.

Zoom: https://ucl.zoom.us/j/97705803853

Talk abstract: The remarkable diversity of neuronal cell types that constitute the nervous system is underpinned by two parallel gene expression programs: (i) neuron type-specific programs, driven by terminal selectors that specify unique neuronal identities, and (ii) pan-neuronal programs, which define functional features common to all neurons, such as synaptic vesicle machinery and neuropeptide processing. While regulators of neuron type-specific programs are well-established, the regulators of pan-neuronal gene expression have remained elusive. Recently, we identified the CUT homeobox gene family as critical regulators of pan-neuronal identity in C. elegans. CUT genes are expressed in all neurons and bind to the regulatory control regions of pan-neuronal genes. Removal of individual CUT genes reveals a dosage-sensitive function of these genes in controlling pan-neuronal gene expression and neuronal function. Extensive neuronal transcriptional profiling in neurons lacking all neuronal CUT genes shows that these factors are essential for the expression of large cohorts of neuronal genes. Further genetic loss-of-function analysis demonstrate that CUT genes cooperate with neuron type-specific transcription factors to control pan-neuronal gene expression. Our current experiments aim to deepen the understanding of this cooperation at the molecular level, focusing on the impact of CUT homeobox genes on chromatin accessibility and their potential influence on the binding of other regulators of neuronal fate. We further dissected the regulation of one of these pan-neuronal regulators, ceh-44/CUX, a CUT homeobox gene whose expression is restricted to the nervous system. Our findings show that ceh-44/CUX is encoded within a complex locus that also produces a Golgi-localized protein, CONE-1, homologous to human CASP. During early embryogenesis, the locus primarily generates CONE-1/CASP across all tissues. However, upon the onset of neuronal terminal differentiation, the RNA splicing factor UNC-75/CELF induces the production of an alternative transcript encoding CEH-44/CUX, restricting its expression to neurons. Together, these findings provide novel insights into how neuronal gene expression programs are specified and reveal a highly buffered and robust mechanism that controls the most critical functional features of all neuronal cell types. At present, we are actively exploring the potential of leveraging these CUT homeobox genes to drive the reprogramming of non-neuronal cells into neurons, offering promising prospects for advancing neuronal identity induction in mammalian systems.

Host: Vil Fernandes