# Investigation of the roles for CaV1.2 in non-excitable tissue during development

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $475,875

## Abstract

Although voltage-gated Ca2+ channels (VGCCs) have been studied extensively for their roles in neurons,
heart, and hormone-secreting cells, the especially broad array of abnormalities in Timothy syndrome (TS)
implies unexpected roles for VGCCs during development. TS is due to a gain-of-function mutation in
CACNA1C, the gene encoding the pore-forming α1C subunit of the L-type Ca2+ channel CaV1.2. Intense focus
on TS has centered on how the mutant channels lead to cardiac arrhythmias or autism, but almost no studies
have examined CaV1.2 contributions to accompanying phenotypes such as syndactyly. Unraveling these
CaV1.2 contributions will be fruitful, since these TS phenotypes include multiple common birth defects, implying
that dysfunctional CaV1.2 signaling generally is a frequent cause of developmental abnormalities. Moreover,
the consequences of dysfunctional CaV1.2 in birth defects demonstrates that CaV1.2 has important, but
understudied roles in normal development. Here we propose three Aims: 1: Test the hypothesis that Ca2+ influx
through TS mutant CaV1.2 affects interdigital apoptosis; 2: Test the hypothesis that Ca2+ influx through CaV1.2
controls bone development; and 3: Test the hypothesis that the developing mouse limb displays electrical
signaling properties that regulate CaV1.2.
 To complete these aims, we have generated various knockin, knockout, and tissue-specific gain-of-function
and loss-of-function mouse models, with which we obtained preliminary data demonstrating roles for CaV1.2
within the developing limb and within developing bone. Further, we have developed methods that build upon
multiple technologies to permit live Ca2+ imaging in ex vivo limb cultures isolated from mouse embryos. These
methods will provide an unprecedented characterization of parameters such as properties of spontaneous and
evoked Ca2+ transients, resting membrane potential, dynamic changes in membrane potential, action
potentials, and VGCC currents in developing limbs.
 Successful completion of these Aims will define novel roles for CaV1.2 in the development of tissues other
than brain, heart, and endocrine tissue, thereby revealing mechanisms for many of the unexplained TS
phenotypes. Because CaV1.2 anchors a large molecular complex, these studies will serve as a platform for
future investigation of the roles of CaV1.2-associated proteins and their downstream signaling partners in
development and whether their dysfunction also contributes to birth defects. The availability of clinically used
agents that target CaV1.2 offers the opportunity to exploit the knowledge gained from the proposed
experiments for new treatment paradigms.

## Key facts

- **NIH application ID:** 10011883
- **Project number:** 5R01HD090132-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Geoffrey S Pitt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $475,875
- **Award type:** 5
- **Project period:** 2016-09-08 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10011883

## Citation

> US National Institutes of Health, RePORTER application 10011883, Investigation of the roles for CaV1.2 in non-excitable tissue during development (5R01HD090132-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10011883. Licensed CC0.

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