Biology subjects

Thulabandu, V.

Publications and source records attributed to Thulabandu, V..

3 recordsLinked to original sources

bioRxiv2026

Active repression of muscle fate preserves neural lineage identity during cerebellum development

Cell fate commitment is commonly thought to entail progressive restriction of developmental potential, enforced by passive, heterochromatin-based silencing of alternative lineage programs. Here we show that maintenance of neural identity during cerebellum development instead requires active repression of a starkly divergent fate by the TEAD-INSM1 transcriptional complex. Loss of TEAD1/2 or INSM1 activates the myogenic master regulator Myod1, resulting in neural cells acquiring transcriptional, structural, and metabolic features of skeletal muscle cells. Deletion of Myod1 fully suppresses neural-to-muscle conversion while partially rescuing neural developmental defects. Our results uncover a latent alternative lineage during neurodevelopment and a surprising role for sequence-specific transcription factors in enforcing lineage boundaries, including those previously thought essentially unbreachable, with implications for understanding aberrant differentiation in disease contexts and cell-type evolution.

developmental biology↗

bioRxiv2026

Insulinoma-associated 1 promotes neurogenic proliferation of cortical basal progenitors but is largely dispensable for projection neuron production

Basal progenitors (BPs) are essential contributors to mammalian cortical neurogenesis, yet the mechanisms governing their behavior remain incompletely understood. Insulinoma-associated 1 (INSM1), a SNAG-domain zinc-finger transcription factor, has been proposed to promote BP generation and expansion, although prior conclusions relied heavily on gain-of-function approaches and were limited by early lethality of Insm1-null embryos. Here, using conditional genetic ablation of Insm1 in mouse cortical progenitors, we reveal that INSM1 is largely dispensable for BP generation but is essential for proper BP cell-cycle progression. INSM1-deficient BPs exhibit impaired S-phase entry, reduced RB phosphorylation, and downregulation of cell-cycle-related gene programs. Although neurogenesis by BPs is diminished, apical progenitors (APs) compensate by increasing symmetric amplifying divisions, expanding the AP pool and preserving production of later-born, upper-layer neurons despite reduced early-born, deep-layer neurons. These findings identify INSM1 as a critical regulator of BP neurogenic proliferation and highlight compensatory flexibility within the cortical progenitor hierarchy. Significance StatementThe developing mammalian cortex contains two principal classes of neural progenitor cells: apical progenitors (APs), which serve as the primary stem/progenitor population; and basal progenitors (BPs), which are produced by APs. The vast majority of cortical neurons are generated by BPs, yet how BP proliferation is regulated remains unclear. We show that Insulinoma-associated 1 (INSM1), previously thought to control BP biogenesis, instead governs BP cell-cycle progression. Loss of INSM1 impairs BP proliferation. However, overall cortical neuron output is largely preserved because APs compensate by expanding their population. Our findings revise the role of INSM1 in cortical development and provide insight into how mammalian neurogenesis maintains robustness through compensatory responses among neural progenitor populations.

neuroscience↗

bioRxiv2024

TEAD promotes lineage progression of subpallial neural progenitor cells independent of YAP/TAZ

The TEAD family of transcription factors are best known as the DNA-binding factor in the Hippo pathway, where they act by interacting with transcriptional coactivators YAP and TAZ (YAP/TAZ). Despite the importance of the Hippo pathway, the in vivo functions of TEAD in mammals have not been well established. By comparing mouse mutants lacking TEAD1 and TEAD2 (TEAD1/2) to those lacking YAP/TAZ, we found that TEAD1/2 have both YAP/TAZ-dependent and -independent functions during ventral telencephalon development. TEAD1/2 loss and YAP/TAZ loss similarly disrupt neuroepithelial apical junctions. However, the impacts of their losses on progenitor lineage progression are essentially opposite: Whereas YAP/TAZ loss depletes early progenitors and increases later progenitors--consistent with their established function in promoting progenitor self-renewal and proliferation, TEAD1/2 loss expands early progenitors and reduces late progenitors, indicating that TEAD1/2 promote lineage progression. We further show that TEAD1/2 promote neural progenitor lineage progression by, at least in part, inhibiting Notch signaling and by cooperating with Insulinoma-associated 1 (INSM1). Orthologs of TEAD and INSM1 have been shown to cooperatively regulate neuronal cell fate decisions in worms and flies. Our study reveals a remarkable evolutionary conservation of the function of this transcription factor complex during metazoan neural development.

developmental biology↗