The transcription factor CREB3L1 is expressed in a wide variety of tissues including cartilage, pancreas, and bone. It is located in the endoplasmic reticulum and upon stimulation is transported to the Golgi where is proteolytically cleaved. Then, the N-terminal domain translocates to the nucleus to activate gene expression. In thyroid follicular cells, CREB3L1 is a downstream effector of thyrotropin (TSH), promoting the expression of proteins of the secretory pathway along with an expansion of the Golgi volume. Here, we analyzed the role of CREB3L1 as a TSH-dependent transcriptional regulator of the expression of the sodium/iodide symporter (NIS), a major thyroid protein that mediates iodide uptake. We show that overexpression and inhibition of CREB3L1 induce an increase and decrease in the NIS protein and mRNA levels, respectively. This, in turn, impacts on NIS-mediated iodide uptake. Furthermore, CREB3L1 knockdown hampers the increase the TSH-induced NIS expression levels. Finally, the ability of CREB3L1 to regulate the promoter activity of the NIS-coding gene (Slc5a5) was confirmed. Taken together, our findings highlight the role of CREB3L1 in maintaining the homeostasis of thyroid follicular cells, regulating the adaptation of the secretory pathway as well as the synthesis of thyroid-specific proteins in response to TSH stimulation.

The transition from a neural progenitor to a mature, polarized neuron requires a substantial and strictly coordinated investment of cellular energy. While the genetic cascades governing cytoskeletal remodeling and structural polarity are well documented, how these programs are metabolically supported during early differentiation remains a fundamental question in neurobiology. In this study, using three different species as study models: rats, mice, and humans and an unbiased transcriptomic approach, we identify the transcription factor CREB3L1 as a key molecular regulator that dynamically modulates both neuronal morphogenesis and cellular bioenergetics. Through targeted CRISPR-Cas9 knockout in human iPSC-derived glutamatergic neurons and functional silencing in rodent models, we demonstrate that the loss of CREB3L1 disrupts critical cytoskeletal networks required for axonogenesis. This structural collapse is accompanied by a bioenergetic paradox: CREB3L1-deficient neurons trigger a compensatory upregulation of mitochondrial biogenesis programs; however, these upregulated networks are functionally defective, exhibiting dissipation of membrane potential and impaired metabolic capacity. In vivo assays using in utero electroporation reveal that this bioenergetic failure delay developing neurons in a multipolar state, thereby impairing the multipolar-to-bipolar transition relevant for proper cortical integration. Collectively, our findings define CREB3L1 as a transcriptional regulator controlling both structural architecture and mitochondrial homeostasis, offering a novel, cross-species framework for understanding neurodevelopmental vulnerabilities and neuropathologies.